text:
@article{Angeles-Albores2018,
author = {Angeles-Albores, David and Lee, Raymon YN and Chan, Juancarlos and Sternberg, Paul W.},
doi = {https://doi.org/10.17912/W25Q2N},
journal = {Micropublication: biology. Dataset.},
mendeley-groups = {AllelicSeries},
title = {{Two new functions in the WormBase Enrichment Suite}},
year = {2018}
}
@article{Eisenmann1998,
abstract = {In C. elegans, the epithelial Pn.p cells adopt either a vulval precursor cell fate or fuse with the surrounding hypodermis (the F fate). Our results suggest that a Wnt signal transduced through a pathway involving the beta-catenin homolog BAR-1 controls whether P3.p through P8.p adopt the vulval precursor cell fate. In bar-1 mutants, P3.p through P8.p can adopt F fates instead of vulval precursor cell fates. The Wnt/bar-1 signaling pathway acts by regulating the expression of the Hox gene lin-39, since bar-1 is required for LIN-39 expression and forced lin-39 expression rescues the bar-1 mutant phenotype. LIN-39 activity is also regulated by the anchor cell signal/let-23 receptor tyrosine kinase/let-60 Ras signaling pathway. Our genetic and molecular experiments show that the vulval precursor cells can integrate the input from the BAR-1 and LET-60 Ras signaling pathways by coordinately regulating activity of the common target LIN-39 Hox.},
author = {Eisenmann, D M and Maloof, J N and Simske, J S and Kenyon, C and Kim, S K},
isbn = {0950-1991 (Print)},
issn = {0950-1991},
journal = {Development (Cambridge, England)},
keywords = {caenorhabditis elegans,hox,vulva,wnt,$\beta$ -catenin},
pages = {3667--3680},
pmid = {9716532},
title = {{The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development.}},
volume = {125},
year = {1998}
}
@article{Kim2006,
abstract = {Signal transduction within the canonical Wnt/beta-catenin pathway drives development and carcinogenesis through programmed or unprogrammed changes in gene transcription. Although the upstream events linked to signal-induced activation of beta-catenin in the cytoplasm have been deciphered in considerable detail, much less is known regarding the mechanism by which beta-catenin stimulates target gene transcription in the nucleus. Here, we show that beta-catenin physically and functionally targets the MED12 subunit in Mediator to activate transcription. The beta-catenin transactivation domain bound directly to isolated MED12 and intact Mediator both in vitro and in vivo, and Mediator was recruited to Wnt-responsive genes in a beta-catenin-dependent manner. Disruption of the beta-catenin/MED12 interaction through dominant-negative interference- or RNA interference-mediated MED12 suppression inhibited beta-catenin transactivation in response to Wnt signaling. This study thus identifies the MED12 interface within Mediator as a new component and a potential therapeutic target in the Wnt/beta-catenin pathway.},
author = {Kim, Seokjoong and Xu, Xuan and Hecht, Andreas and Boyer, Thomas G},
doi = {10.1074/jbc.M602696200},
file = {:Users/dangeles/Documents/Mendeley Desktop/Kim et al. - 2006 - Mediator is a transducer of Wntbeta-catenin signaling.pdf:pdf},
isbn = {2105677258},
issn = {00219258},
journal = {Journal of Biological Chemistry},
mendeley-groups = {AllelicSeries},
month = {may},
number = {20},
pages = {14066--14075},
pmid = {16565090},
publisher = {American Society for Biochemistry and Molecular Biology},
title = {{Mediator is a transducer of Wnt/$\beta$-catenin signaling}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16565090},
volume = {281},
year = {2006}
}
@article{Graham2013,
abstract = {MED12: is a member of the large Mediator complex, which has a critical and central role in RNA polymerase II transcription. As a multiprotien complex, Mediator regulates signals involved in cell growth, development, and differentiation, and it is involved in a protein network required for extraneuronal gene silencing and also functions as a direct suppressor of Gli3-dependent Sonic hedgehog signaling. This may explain its role in several different X-linked intellectual disability syndromes that share some overlapping clinical features. This review will compare and contrast four different clinical conditions that have been associated with different mutations in MED12, which is located at Xq13. To date, these conditions include Opitz-Kaveggia (FG) syndrome, Lujan syndrome, Ohdo syndrome (Maat-Kievit-Brunner type, or OSMKB), and one large family with profound X-linked intellectual disability due to a novel c.5898insC frameshift mutation that unlike the other three syndromes, resulted in affected female carriers and truncation of the MED12 protein. It is likely that more MED12 mutations will be detected in sporadic patients and X-linked families with intellectual disability and dysmorphic features as exome sequencing becomes more commonly utilized, and this overview of MED12-related disorders may help to correlate MED12 genotypes with clinical findings.},
author = {Graham, John M. and Schwartz, Charles E.},
doi = {10.1002/ajmg.a.36183},
isbn = {6176321972},
issn = {15524825},
journal = {American Journal of Medical Genetics, Part A},
keywords = {FG syndrome,Lujan-Fryns syndrome,MED12,Ohdo syndrome (Maat-Kievit-Brunner type),Opitz-Kaveggia syndrome,X-linked intellectual disability},
month = {nov},
number = {11},
pages = {2734--2740},
pmid = {24123922},
title = {{MED12 related disorders}},
volume = {161},
year = {2013}
}
@article{Yamamoto2015,
abstract = {A novel MED12 mutation associated with non-specific X-linked intellectual disability},
author = {Yamamoto, Toshiyuki and Shimojima, Keiko},
doi = {10.1038/hgv.2015.18},
file = {:Users/dangeles/Documents/Mendeley Desktop/Yamamoto, Shimojima - 2015 - A novel MED12 mutation associated with non-specific X-linked intellectual disability.pdf:pdf},
isbn = {9196805536},
issn = {2054-345X},
journal = {Human Genome Variation},
keywords = {Disease genetics},
mendeley-groups = {AllelicSeries},
month = {jun},
pages = {15018},
publisher = {Nature Publishing Group},
title = {{A novel MED12 mutation associated with non-specific X-linked intellectual disability}},
volume = {2},
year = {2015}
}
@article{Kim2006,
abstract = {Signal transduction within the canonical Wnt/beta-catenin pathway drives development and carcinogenesis through programmed or unprogrammed changes in gene transcription. Although the upstream events linked to signal-induced activation of beta-catenin in the cytoplasm have been deciphered in considerable detail, much less is known regarding the mechanism by which beta-catenin stimulates target gene transcription in the nucleus. Here, we show that beta-catenin physically and functionally targets the MED12 subunit in Mediator to activate transcription. The beta-catenin transactivation domain bound directly to isolated MED12 and intact Mediator both in vitro and in vivo, and Mediator was recruited to Wnt-responsive genes in a beta-catenin-dependent manner. Disruption of the beta-catenin/MED12 interaction through dominant-negative interference- or RNA interference-mediated MED12 suppression inhibited beta-catenin transactivation in response to Wnt signaling. This study thus identifies the MED12 interface within Mediator as a new component and a potential therapeutic target in the Wnt/beta-catenin pathway.},
author = {Kim, Seokjoong and Xu, Xuan and Hecht, Andreas and Boyer, Thomas G},
doi = {10.1074/jbc.M602696200},
file = {:Users/dangeles/Documents/Mendeley Desktop/Kim et al. - 2006 - Mediator is a transducer of Wntbeta-catenin signaling.pdf:pdf},
isbn = {2105677258},
issn = {00219258},
journal = {Journal of Biological Chemistry},
mendeley-groups = {AllelicSeries},
month = {may},
number = {20},
pages = {14066--14075},
pmid = {16565090},
publisher = {American Society for Biochemistry and Molecular Biology},
title = {{Mediator is a transducer of Wnt/$\beta$-catenin signaling}},
volume = {281},
year = {2006}
}
@article{Schwarz2012,
abstract = {In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi-treated L4 larvae. We observed expression of 8,000-10,000 genes in the linker cell, 22-25{\%} of which were up- or down-regulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22{\%} (45 of 204) were required for normal shape and migration, suggesting that many NHR-67-dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.},
author = {Schwarz, Erich M. and Kato, Mihoko and Sternberg, Paul W.},
doi = {10.1073/pnas.1203045109},
file = {:Users/dangeles/Documents/Mendeley Desktop/Schwarz, Kato, Sternberg - 2012 - Functional transcriptomics of a migrating cell in Caenorhabditis elegans.pdf:pdf;:Users/dangeles/Documents/Mendeley Desktop/Schwarz, Kato, Sternberg - 2012 - Functional transcriptomics of a migrating cell in Caenorhabditis elegans(2).pdf:pdf},
isbn = {1091-6490 (Electronic)$\backslash$r0027-8424 (Linking)},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {Animals,Caenorhabditis elegans,Caenorhabditis elegans: growth {\&} development,Cell Movement,Cell Movement: genetics,Cell Movement: physiology,Developmental,Developmental: physiol,Gene Expression Regulation,Gonads,Gonads: cytology,Larva,Larva: physiology,Male,Organogenesis,Organogenesis: physiology,RNA Interference,Reverse Transcriptase Polymerase Chain Reaction,Transcriptome,Transcriptome: genetics},
mendeley-groups = {PastPapers/MPRSQ},
month = {oct},
number = {40},
pages = {16246--51},
pmid = {22991463},
title = {{Functional transcriptomics of a migrating cell in \emph{Caenorhabditis elegans}.}},
volume = {109},
year = {2012}
}

@article{Edgar2002,
abstract = {The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expression databases that benefit from coherent data sets, and which are constructed to facilitate a particular analytic method, but rather complement these by acting as a tertiary, central data distribution hub. The three central data entities of GEO are platforms, samples and series, and were designed with gene expression and genomic hybridization experiments in mind. A platform is, essentially, a list of probes that define what set of molecules may be detected. A sample describes the set of molecules that are being probed and references a single platform used to generate its molecular abundance data. A series organizes samples into the meaningful data sets which make up an experiment. The GEO repository is publicly accessible through the World Wide Web at http://www.ncbi.nlm.nih.gov/geo.},
author = {Edgar, Ron and Domrachev, Michael and Lash, Alex E},
issn = {1362-4962},
journal = {Nucleic acids research},
mendeley-groups = {AllelicSeries},
month = {jan},
number = {1},
pages = {207--10},
pmid = {11752295},
publisher = {Oxford University Press},
title = {{Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.}},
volume = {30},
year = {2002}
}

@article{Cao2017,
abstract = {To resolve cellular heterogeneity, we developed a combinatorial indexing strategy to profile the transcriptomes of single cells or nuclei, termed sci-RNA-seq (single-cell combinatorial indexing RNA sequencing). We applied sci-RNA-seq to profile nearly 50,000 cells from the nematode \emph{Caenorhabditis~elegans} at the L2 larval stage, which provided {\textgreater}50-fold "shotgun" cellular coverage of its somatic cell composition. From these data, we defined consensus expression profiles for 27 cell types and recovered rare neuronal cell types corresponding to as few as one or two cells in the L2 worm. We integrated these profiles with whole-animal chromatin immunoprecipitation sequencing data to deconvolve the cell type-specific effects of transcription factors. The data generated by sci-RNA-seq constitute a powerful resource for nematode biology and foreshadow similar atlases for other organisms.},
author = {Cao, Junyue and Packer, Jonathan S and Ramani, Vijay and Cusanovich, Darren A and Huynh, Chau and Daza, Riza and Qiu, Xiaojie and Lee, Choli and Furlan, Scott N and Steemers, Frank J and Adey, Andrew and Waterston, Robert H and Trapnell, Cole and Shendure, Jay},
doi = {10.1126/science.aam8940},
file = {:Users/dangeles/Documents/Mendeley Desktop/Cao et al. - 2017 - Comprehensive single-cell transcriptional profiling of a multicellular organism.pdf:pdf},
issn = {1095-9203},
journal = {Science (New York, N.Y.)},
mendeley-groups = {AllelicSeries},
month = {aug},
number = {6352},
pages = {661--667},
pmid = {28818938},
publisher = {American Association for the Advancement of Science},
title = {{Comprehensive single-cell transcriptional profiling of a multicellular organism.}},
volume = {357},
year = {2017}
}

@article{Hodgkin1979,
author = {Hodgkin, Jonathan and Horvitz, H. Robert and Brenner, Sydney},
journal = {Genetics},
mendeley-groups = {AllelicSeries},
number = {1},
title = {{NONDISJUNCTION MUTANTS OF THE NEMATODE \emph{Caenorhabditis~elegans}}},
volume = {91},
year = {1979}
}
@article{Meneely1987,
author = {Meneely, Philip M. and Wood, William B.},
journal = {Genetics},
mendeley-groups = {AllelicSeries},
number = {1},
title = {{Genetic Analysis of X-Chromosome Dosage Compensation in \emph{Caenorhabditis~elegans}}},
volume = {117},
year = {1987}
}

@article{Brenner1974,
abstract = {Methods are described for the isolation, complementation and mapping of mutants of \emph{Caenorhabditis~elegans}, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in \emph{C.~elegans} are large.},
author = {Brenner, S.},
issn = {0016-6731},
journal = {Genetics},
mendeley-groups = {AllelicSeries},
number = {1},
pages = {71--94},
title = {{The Genetics of \emph{Caenorhabditis~elegans}}},
volume = {77},
year = {1974}
}

@article{Yook2005,
abstract = {Mutations in many genes can result in a similar phenotype. Finding a number of mutants with the same phenotype tells you little about how many genes you are dealing with, and how mutable those genes are until you can assign those mutations to genetic loci. The genetic assay for gene assignment is called the complementation test. The simplicity and robustness of this test makes it a fundamental genetic tool for gene assignment. However, there are occasional unexpected outcomes from this test that bear explanation. This chapter reviews the complementation test and its various outcomes, highlighting relatively rare but nonetheless interesting exceptions such as intragenic complementation and non-allelic non-complementation.},
author = {Yook, Karen},
doi = {10.1895/wormbook.1.24.1},
isbn = {1551-8507},
issn = {15518507},
journal = {WormBook},
mendeley-groups = {AllelicSeries},
pmid = {18023121},
title = {{Complementation}},
year = {2005}
}

@misc{Chiu2013,
abstract = {CRISPR-Cas is an efficient method for genome editing in organisms from bacteria to human cells. We describe a transgene-free method for CRISPR-Cas-mediated cleavage in nematodes, enabling RNA-homology-targeted deletions that cause loss of gene function; analysis of whole-genome sequencing indicates that the nuclease activity is highly specific.},
author = {Chiu, Hui and Schwartz, Hillel T and Antoshechkin, Igor and Sternberg, Paul W},
booktitle = {Genetics},
doi = {10.1534/genetics.113.155879},
file = {:Users/dangeles/Documents/Mendeley Desktop/Chiu et al. - 2013 - Transgene-free genome editing in \emph{Caenorhabditis~elegans} using CRISPR-Cas.pdf:pdf},
isbn = {1943-2631 (Electronic)$\backslash$r0016-6731 (Linking)},
issn = {00166731},
keywords = {CRISPR,Caenorhabditis elegans,genome resequencing,reverse genetics,targeted nuclease},
mendeley-groups = {AllelicSeries},
month = {nov},
number = {3},
pages = {1167--1171},
pmid = {23979577},
publisher = {Genetics},
title = {{Transgene-free genome editing in \emph{Caenorhabditis~elegans} using CRISPR-Cas}},
volume = {195},
year = {2013}
}

@article{Storey2003,
abstract = {With the increase in genomewide experiments and the sequencing of multiple genomes, the analysis of large data sets has become commonplace in biology. It is often the case that thousands of features in a genomewide data set are tested against some null hypothesis, where a number of features are expected to be significant. Here we propose an approach to measuring statistical significance in these genomewide studies based on the concept of the false discovery rate. This approach offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted. In doing so, a measure of statistical significance called the q value is associated with each tested feature. The q value is similar to the well known p value, except it is a measure of significance in terms of the false discovery rate rather than the false positive rate. Our approach avoids a flood of false positive results, while offering a more liberal criterion than what has been used in genome scans for linkage.},
author = {Storey, John D and Tibshirani, Robert},
doi = {10.1073/pnas.1530509100},
file = {:Users/dangeles/Documents/Mendeley Desktop/Storey, Tibshirani - 2003 - Statistical significance for genomewide studies.pdf:pdf},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
mendeley-groups = {AllelicSeries},
month = {aug},
number = {16},
pages = {9440--5},
pmid = {12883005},
publisher = {National Academy of Sciences},
title = {{Statistical significance for genomewide studies.}},
volume = {100},
year = {2003}
}
@misc{Benjamini1995,
abstract = {The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses-the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferroni-type procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.},
author = {Benjamini, Yoav and Hochberg, Yosef},
booktitle = {Journal of the Royal Statistical Society. Series B (Methodological)},
doi = {10.2307/2346101},
keywords = {Applied statistics,Error rates,False positive errors,Mathematical procedures,Mortality,Null hypothesis,P values,Random variables,Simulations,Statistics},
mendeley-groups = {AllelicSeries},
pages = {289--300},
publisher = {WileyRoyal Statistical Society},
title = {{Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing}},
volume = {57},
year = {1995}
}

@article{Bourbon2004,
author = {Bourbon, Henri-Marc and Aguilera, Andres and Ansari, Aseem Z. and Asturias, Francisco J. and Berk, Arnold J. and Bjorklund, Stefan and Blackwell, T.Keith and Borggrefe, Tilman and Carey, Michael and Carlson, Marian and Conaway, Joan W. and Conaway, Ronald C. and Emmons, Scott W. and Fondell, Joseph D. and Freedman, Leonard P. and Fukasawa, Toshio and Gustafsson, Claes M. and Han, Min and He, Xi and Herman, Paul K. and Hinnebusch, Alan G. and Holmberg, Steen and Holstege, Frank C. and Jaehning, Judith A. and Kim, Young-Joon and Kuras, Laurent and Leutz, Achim and Lis, John T. and Meisterernest, Michael and Naar, Anders M. and Nasmyth, Kim and Parvin, Jeffrey D. and Ptashne, Mark and Reinberg, Danny and Ronne, Hans and Sadowski, Ivan and Sakurai, Hiroshi and Sipiczki, Matthias and Sternberg, Paul W. and Stillman, David J. and Strich, Randy and Struhl, Kevin and Svejstrup, Jasper Q. and Tuck, Simon and Winston, Fred and Roeder, Robert G. and Kornberg, Roger D.},
doi = {10.1016/j.molcel.2004.05.011},
issn = {10972765},
journal = {Molecular Cell},
mendeley-groups = {AllelicSeries},
month = {jun},
number = {5},
pages = {553--557},
title = {{A Unified Nomenclature for Protein Subunits of Mediator Complexes Linking Transcriptional Regulators to RNA Polymerase II}},
volume = {14},
year = {2004}
}
@article{AngelesAlboresHIF,
abstract = {RNA-sequencing (RNA-seq) is commonly used to identify genetic modules that respond to perturbations. In single cells, transcriptomes have been used as phenotypes, but this concept has not been applied to whole-organism RNA-seq. Also, quantifying and interpreting epistatic effects using expression profiles remains a challenge. We developed a single coefficient to quantify transcriptome-wide epistasis that reflects the underlying interactions and which can be interpreted intuitively. To demonstrate our approach, we sequenced four single and two double mutants of Caenorhabditis elegans From these mutants, we reconstructed the known hypoxia pathway. In addition, we uncovered a class of 56 genes with HIF-1-dependent expression that have opposite changes in expression in mutants of two genes that cooperate to negatively regulate HIF-1 abundance; however, the double mutant of these genes exhibits suppression epistasis. This class violates the classical model of HIF-1 regulation but can be explained by postulating a role of hydroxylated HIF-1 in transcriptional control.},
author = {Angeles-Albores, David and {Puckett Robinson}, Carmie and Williams, Brian A and Wold, Barbara J and Sternberg, Paul W},
doi = {10.1073/pnas.1712387115},
file = {:Users/dangeles/Documents/Mendeley Desktop/Angeles-Albores et al. - 2018 - Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements.pdf:pdf},
issn = {1091-6490},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {epistasis,gene expression,genetics,hypoxia,transcriptomics},
mendeley-groups = {AllelicSeries},
month = {mar},
number = {13},
pages = {E2930--E2939},
pmid = {29531064},
publisher = {National Academy of Sciences},
title = {{Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/29531064 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC5879656},
volume = {115},
year = {2018}
}
@article{Greenwald1983,
abstract = {We describe two classes of mutations in the lin-12 locus of the nematode \emph{Caenorhabditis~elegans}. Ten semidominant mutations (lin-12[d]) appear to elevate the level of lin-12 activity. Thirty-two recessive alleles (lin-12[0]), including two amber mutations, appear to eliminate gene activity. The lin-12(d) and lin-12(0) mutations result in reciprocal homeotic transformations in the fates of defined cells in several different tissues. Gene dosage studies suggest that a high level of lin-12 activity specifies one cell fate and a low level specifies an alternative fate. Temperature-shift experiments indicate that lin-12 acts at the time cell fate is determined in wild type. We propose that lin-12 functions as a binary switch to control decisions between alternative cell fates during \emph{C.~elegans} development. ?? 1983.},
author = {Greenwald, Iva S. and Sternberg, Paul W. and {Robert Horvitz}, H.},
doi = {10.1016/0092-8674(83)90377-X},
file = {:Users/dangeles/Documents/Mendeley Desktop/Unknown - 1983 - The lin-12 locus specifies cell fates in \emph{Caenorhabditis~elegans}.pdf:pdf},
isbn = {0092-8674 (Print)$\backslash$n0092-8674 (Linking)},
issn = {00928674},
journal = {Cell},
mendeley-groups = {AllelicSeries},
month = {sep},
number = {2},
pages = {435--444},
pmid = {6616618},
publisher = {Cell Press},
title = {{The lin-12 locus specifies cell fates in \emph{Caenorhabditis~elegans}}},
volume = {34},
year = {1983}
}
@article{Aroian1991,
abstract = {The let-23 gene, which encodes a putative tyrosine kinase of the epidermal growth factor (EGF) receptor subfamily, has multiple functions during \emph{Caenorhabditis~elegans} development. We show that let-23 function is required for vulval precursor cells (VPCs) to respond to the signal that induces vulval differentiation: a complete loss of let-23 function results in no induction. However, some let-23 mutations that genetically reduce but do not eliminate let-23 function result in VPCs apparently hypersensitive to inductive signal: as many as five of six VPCs can adopt vulval fates, in contrast to the three that normally do. These results suggest that the let-23 receptor tyrosine kinase controls two opposing pathways, one that stimulates vulval differentiation and another that negatively regulates vulval differentiation. Furthermore, analysis of 16 new let-23 mutations indicates that the let-23 kinase functions in at least five tissues. Since various let-23 mutant phenotypes can be obtained independently, the let-23 gene is likely to have tissue-specific functions.},
author = {Aroian, Raffi V and Sternberg, Paul W},
issn = {0016-6731},
journal = {Genetics},
keywords = {Alleles,Animals,Caenorhabditis,Caenorhabditis: genetics,Caenorhabditis: growth {\&} development,Caenorhabditis: physiology,Cell Differentiation,Cell Differentiation: genetics,Epidermal Growth Factor,Epidermal Growth Factor: genetics,Female,Genetic Complementation Test,Mutation,Organ Specificity,Organ Specificity: genetics,Phenotype,Protein-Tyrosine Kinases,Protein-Tyrosine Kinases: genetics,Receptor,Vulva,Vulva: cytology,Vulva: growth {\&} development},
mendeley-groups = {AllelicSeries},
number = {2},
pages = {251--67},
pmid = {2071015},
title = {{Multiple functions of let-23, a \emph{Caenorhabditis~elegans} receptor tyrosine kinase gene required for vulval induction.}},
volume = {128},
year = {1991}
}
@article{Ferguson1985a,
author = {Ferguson, E and Horvitz, H. Robert},
journal = {Genetics},
mendeley-groups = {AllelicSeries},
number = {1},
pages = {17--72},
title = {{Identification and characterization of 22 genes that affect the vulval cell lineages of \emph{Caenorhabditis~elegans}}},
volume = {110},
year = {1985}
}

@article{Rozenblatt-Rosen2017,
author = {Rozenblatt-Rosen, Orit and Stubbington, Michael J. T. and Regev, Aviv and Teichmann, Sarah A.},
doi = {10.1038/550451a},
issn = {1476-4687},
journal = {Nature},
mendeley-groups = {AllelicSeries},
month = {oct},
title = {{The Human Cell Atlas: from vision to reality}},
year = {2017}
}
@article{Lane2017,
abstract = {Signaling proteins display remarkable cell-to-cell heterogeneity in their dynamic responses to stimuli, but the consequences of this heterogeneity remain largely unknown. For instance, the contribution of the dynamics of the innate immune transcription factor nuclear factor $\kappa$B (NF-$\kappa$B) to gene expression output is disputed. Here we explore these questions by integrating live-cell imaging approaches with single-cell sequencing technologies. We used this approach to measure both the dynamics of lipopolysaccharide-induced NF-$\kappa$B activation and the global transcriptional response in the same individual cell. Our results identify multiple, distinct cytokine expression patterns that are correlated with NF-$\kappa$B activation dynamics, establishing a functional role for NF-$\kappa$B dynamics in determining cellular phenotypes. Applications of this approach to other model systems and single-cell sequencing technologies have significant potential for discovery, as it is now possible to trace cellular behavior from the initial stimulus, through the signaling pathways, down to genome-wide changes in gene expression, all inside of a single cell.},
author = {Lane, Keara and {Van Valen}, David and DeFelice, Mialy M. and Macklin, Derek N. and Kudo, Takamasa and Jaimovich, Ariel and Carr, Ambrose and Meyer, Tobias and Pe'er, Dana and Boutet, St{\'{e}}phane C. and Covert, Markus W.},
doi = {10.1016/j.cels.2017.03.010},
issn = {24054712},
journal = {Cell Systems},
mendeley-groups = {AllelicSeries},
month = {apr},
number = {4},
pages = {458--469.e5},
title = {{Measuring Signaling and RNA-Seq in the Same Cell Links Gene Expression to Dynamic Patterns of NF-$\kappa$B Activation}},
volume = {4},
year = {2017}
}

@article{Tang2009,
author = {Tang, Fuchou and Barbacioru, Catalin and Wang, Yangzhou and Nordman, Ellen and Lee, Clarence and Xu, Nanlan and Wang, Xiaohui and Bodeau, John and Tuch, Brian B and Siddiqui, Asim and Lao, Kaiqin and Surani, M Azim},
doi = {10.1038/nmeth.1315},
issn = {1548-7091},
journal = {Nature Methods},
mendeley-groups = {AllelicSeries},
month = {may},
number = {5},
pages = {377--382},
publisher = {Nature Publishing Group},
title = {{mRNA-Seq whole-transcriptome analysis of a single cell}},
volume = {6},
year = {2009}
}
@article{VandePeppel2005,
abstract = {Mediator is an evolutionarily conserved coregulator of RNA polymerase II transcription. Microarray structure-function analysis of S. cerevisiae Mediator reveals functional antagonism between the cyclin-dependent kinase (Cdk) submodule and components from the Tail (Med15, Med2, Med3), Head (Med20, Med18), and Middle (Med31). Certain genes exhibit increased or decreased expression, depending on which subunit is deleted. Epistasis analysis with expression-profile phenotypes shows that MED2 and MED18 are downstream of CDK8. Strikingly, Cdk8-mediated modification of a single amino acid within Mediator represses the regulon of a single transcription factor, Rcs1/Aft1. Highly specific gene regulation is thought to be determined by activators and combinatorial use of cofactors. Here, subtle modification of the general transcription machinery through one of its own components is shown to determine highly specific expression patterns. Expression profiling can therefore precisely map regulatory cascades, and our findings support a role for Mediator as a direct processor of signaling pathways for determining specificity.},
author = {van de Peppel, Jeroen and Kettelarij, Nienke and van Bakel, Harm and Kockelkorn, Thessa T.J.P. and van Leenen, Dik and Holstege, Frank C.P.},
doi = {10.1016/j.molcel.2005.06.033},
issn = {10972765},
journal = {Molecular Cell},
mendeley-groups = {AllelicSeries},
month = {aug},
number = {4},
pages = {511--522},
title = {{Mediator Expression Profiling Epistasis Reveals a Signal Transduction Pathway with Antagonistic Submodules and Highly Specific Downstream Targets}},
volume = {19},
year = {2005}
}
@misc{Jeronimo2017,
abstract = {Mediator is an essential, large, multisubunit, transcriptional co-activator highly conserved across eukaryotes. Mediator interacts with gene-specific transcription factors at enhancers as well as with the RNA polymerase II (RNAPII) transcription machinery bound at promoters. It also interacts with several other factors involved in various aspects of transcription, chromatin regulation, and mRNA processing. Hence, Mediator is at the nexus of RNAPII transcription, regulating its many steps and connecting transcription with co-transcriptional events. To achieve this flexible role, Mediator, which is divided into several functional modules, reorganizes its conformation and composition while making transient contacts with other components. Here, we review the mechanisms of action of Mediator and propose a unifying model for its function. Mediator is implicated in most aspects of gene expression, including nearly all steps of the transcription reaction, in addition to mRNA processing, higher-order chromatin organization, and genome stability.The dynamic composition and structure of Mediator have recently begun to be elucidated through both structural work and in vivo protein-DNA interaction mapping.The Kinase module has both positive and negative roles in gene expression regulation.},
author = {Jeronimo, C{\'{e}}lia and Robert, Fran{\c{c}}ois},
booktitle = {Trends in Cell Biology},
doi = {10.1016/j.tcb.2017.07.001},
issn = {18793088},
keywords = {CDK8,CTD,Mediator,P-TEFb,Pre-initiation complex,RNA polymerase II},
mendeley-groups = {AllelicSeries},
month = {oct},
number = {10},
pages = {765--783},
pmid = {28778422},
publisher = {Elsevier Current Trends},
title = {{The Mediator Complex: At the Nexus of RNA Polymerase II Transcription}},
volume = {27},
year = {2017}
}
@article{Yachdav2014,
author = {Yachdav, G. and Kloppmann, E. and Kajan, L. and Hecht, M. and Goldberg, T. and Hamp, T. and Honigschmid, P. and Schafferhans, A. and Roos, M. and Bernhofer, M. and Richter, L. and Ashkenazy, H. and Punta, M. and Schlessinger, A. and Bromberg, Y. and Schneider, R. and Vriend, G. and Sander, C. and Ben-Tal, N. and Rost, B.},
doi = {10.1093/nar/gku366},
file = {:Users/dangeles/Documents/Mendeley Desktop/Yachdav et al. - 2014 - PredictProtein--an open resource for online prediction of protein structural and functional features.pdf:pdf},
issn = {0305-1048},
journal = {Nucleic Acids Research},
keywords = {amino acid sequence,binding sites,bioinformatics,disulfides,dna,genes,inference,point mutation,polynucleotides,protein binding,protein structure, secondary,rna,sequence alignment,sequence analysis,single nucleotide polymorphism,software,solvents},
mendeley-groups = {AllelicSeries},
month = {jul},
number = {W1},
pages = {W337--W343},
publisher = {Technische Universit{\"{a}}t M{\"{u}}nchen, Munich, Germany},
title = {{PredictProtein--an open resource for online prediction of protein structural and functional features}},
volume = {42},
year = {2014}
}
@article{Hu,
abstract = {Background: Mapping of orthologous genes among species serves an important role in functional genomics by allowing researchers to develop hypotheses about gene function in one species based on what is known about the functions of orthologs in other species. Several tools for predicting orthologous gene relationships are available. However, these tools can give different results and identification of predicted orthologs is not always straightforward. Results: We report a simple but effective tool, the Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool (DIOPT; http://www.flyrnai.org/diopt), for rapid identification of orthologs. DIOPT integrates existing approaches, facilitating rapid identification of orthologs among human, mouse, zebrafish, \emph{C.~elegans}, Drosophila, and S. cerevisiae. As compared to individual tools, DIOPT shows increased sensitivity with only a modest decrease in specificity. Moreover, the flexibility built into the DIOPT graphical user interface allows researchers with different goals to appropriately 'cast a wide net' or limit results to highest confidence predictions. DIOPT also displays protein and domain alignments, including percent amino acid identity, for predicted ortholog pairs. This helps users identify the most appropriate matches among multiple possible orthologs. To facilitate using model organisms for functional analysis of human disease-associated genes, we used DIOPT to predict high-confidence orthologs of disease genes in Online Mendelian Inheritance in Man (OMIM) and genes in genome-wide association study (GWAS) data sets. The results are accessible through the DIOPT diseases and traits query tool (DIOPT-DIST; http://www.flyrnai.org/diopt-dist). Conclusions: DIOPT and DIOPT-DIST are useful resources for researchers working with model organisms, especially those who are interested in exploiting model organisms such as Drosophila to study the functions of human disease genes. Background},
author = {Hu, Yanhui and Flockhart, Ian and Vinayagam, Arunachalam and Bergwitz, Clemens and Berger, Bonnie and Perrimon, Norbert and Mohr, Stephanie E},
doi = {10.1186/1471-2105-12-357},
file = {:Users/dangeles/Documents/Mendeley Desktop/Hu et al. - Unknown - An integrative approach to ortholog prediction for disease-focused and other functional studies.pdf:pdf},
mendeley-groups = {AllelicSeries},
title = {{An integrative approach to ortholog prediction for disease-focused and other functional studies}},
}
@article{Dixit2016,
author = {Dixit, Atray and Parnas, Oren and Li, Biyu and Chen, Jenny and Fulco, Charles P. and Jerby-Arnon, Livnat and Marjanovic, Nemanja D. and Dionne, Danielle and Burks, Tyler and Raychowdhury, Raktima and Adamson, Britt and Norman, Thomas M. and Lander, Eric S. and Weissman, Jonathan S. and Friedman, Nir and Regev, Aviv},
doi = {10.1016/j.cell.2016.11.038},
file = {:Users/dangeles/Documents/Mendeley Desktop/Dixit et al. - 2016 - Perturb-Seq Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens.pdf:pdf},
issn = {00928674},
journal = {Cell},
mendeley-groups = {PastPapers/Fog2Aging,PastPapers/MPRSQ,AllelicSeries},
number = {7},
pages = {1853--1866.e17},
pmid = {27984732},
publisher = {Elsevier Inc.},
title = {{Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens}},
volume = {167},
year = {2016}
}

@article{Villani2017a,
abstract = {Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of {\~{}}2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C(+) subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.},
author = {Villani, Alexandra-Chlo{\'{e}} and Satija, Rahul and Reynolds, Gary and Sarkizova, Siranush and Shekhar, Karthik and Fletcher, James and Griesbeck, Morgane and Butler, Andrew and Zheng, Shiwei and Lazo, Suzan and Jardine, Laura and Dixon, David and Stephenson, Emily and Nilsson, Emil and Grundberg, Ida and McDonald, David and Filby, Andrew and Li, Weibo and {De Jager}, Philip L. and Rozenblatt-Rosen, Orit and Lane, Andrew A. and Haniffa, Muzlifah and Regev, Aviv and Hacohen, Nir},
doi = {10.1126/science.aah4573},
issn = {0036-8075},
journal = {Science},
mendeley-groups = {AllelicSeries},
number = {6335},
pages = {eaah4573},
pmid = {28428369},
title = {{Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors}},
volume = {356},
year = {2017}
}

@article{Angeles-Albores2017,
author = {Angeles-Albores, David and Leighton, Daniel H. W. and Tsou, Tiffany and Khaw, Tiffany H. and Antoshechkin, Igor and Sternberg, Paul W.},
journal = {G3: Genes, Genomes, Genetics},
mendeley-groups = {GeneticsTheory,AllelicSeries},
title = {{The \emph{Caenorhabditis~elegans} Female State: Decoupling the Transcriptomic Effects of Aging and Sperm-Status}},
year = {2017}
}

@article{Mortazavi2008,
abstract = {We have mapped and quantified mouse transcriptomes by deeply sequencing them and recording how frequently each gene is represented in the sequence sample (RNA-Seq). This provides a digital measure of the presence and prevalence of transcripts from known and previously unknown genes. We report reference measurements composed of 41-52 million mapped 25-base-pair reads for poly(A)-selected RNA from adult mouse brain, liver and skeletal muscle tissues. We used RNA standards to quantify transcript prevalence and to test the linear range of transcript detection, which spanned five orders of magnitude. Although {\textgreater}90{\%} of uniquely mapped reads fell within known exons, the remaining data suggest new and revised gene models, including changed or additional promoters, exons and 3' untranscribed regions, as well as new candidate microRNA precursors. RNA splice events, which are not readily measured by standard gene expression microarray or serial analysis of gene expression methods, were detected directly by mapping splice-crossing sequence reads. We observed 1.45 x 10(5) distinct splices, and alternative splices were prominent, with 3,500 different genes expressing one or more alternate internal splices.},
archivePrefix = {arXiv},
arxivId = {1111.6189v1},
author = {Mortazavi, Ali and Williams, Brian A and McCue, Kenneth and Schaeffer, Lorian and Wold, Barbara},
doi = {10.1038/nmeth.1226},
isbn = {1548-7105 (Electronic)$\backslash$r1548-7091 (Linking)},
issn = {1548-7091},
journal = {Nature Methods},
mendeley-groups = {PastPapers/MPRSQ,PastPapers/Fog2Aging,PastPapers/PEA,AllelicSeries},
number = {7},
pages = {621--628},
pmid = {18516045},
title = {{Mapping and quantifying mammalian transcriptomes by RNA-Seq}},
volume = {5},
year = {2008}
}

@article{FINCHAM1957,
author = {FINCHAM, J. R. S. and PATEMAN, J. A.},
doi = {10.1038/179741a0},
issn = {0028-0836},
journal = {Nature},
mendeley-groups = {AllelicSeries},
month = {Apr},
number = {4562},
pages = {741--742},
publisher = {Nature Publishing Group},
title = {{Formation of an Enzyme through Complementary Action of Mutant ‘Alleles' in Separate Nuclei in a Heterocaryon}},
volume = {179},
year = {1957}
}

@article{McClintock1944,
author = {McClintock, Barbara},
journal = {Genetics},
mendeley-groups = {AllelicSeries},
number = {5},
pages = {478--502},
title = {{THE RELATION OF HOMOZYGOUS DEFICIENCIES TO MUTATIONS AND ALLELIC SERIES IN MAIZE}},
volume = {29},
year = {1944}
}

@article{Ewels2016,
abstract = {MOTIVATION Fast and accurate quality control is essential for studies involving next-generation sequencing data. Whilst numerous tools exist to quantify QC metrics, there is no common approach to flexibly integrate these across tools and large sample sets. Assessing analysis results across an entire project can be time consuming and error prone; batch effects and outlier samples can easily be missed in the early stages of analysis. RESULTS We present MultiQC, a tool to create a single report visualising output from multiple tools across many samples, enabling global trends and biases to be quickly identified. MultiQC can plot data from many common bioinformatics tools and is built to allow easy extension and customization. AVAILABILITY MultiQC is available with an GNU GPLv3 license on GitHub, the Python Package Index and Bioconda. Documentation and example reports available at http://multiqc.info CONTACT: phil.ewels@scilifelab.se.},
author = {Ewels, Philip and Magnusson, Mr{\{}a{\}}ns and Lundin, Sverker and K\"{a}ller, Max},
doi = {10.1093/bioinformatics/btw354},
isbn = {13674811 (Electronic)},
issn = {14602059},
journal = {Bioinformatics},
mendeley-groups = {AllelicSeries},
number = {19},
pages = {3047--3048},
pmid = {27312411},
title = {{MultiQC: Summarize analysis results for multiple tools and samples in a single report}},
volume = {32},
year = {2016}
}

@article{Langmead2009,
abstract = {Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source http://bowtie.cbcb.umd.edu.},
author = {Langmead, Ben and Trapnell, Cole and Pop, Mihai and Salzberg, Steven L},
doi = {10.1186/gb-2009-10-3-r25},
journal = {Genome biology},
mendeley-groups = {AllelicSeries},
number = {10},
pages = {R25},
title = {{Bowtie: An ultrafast memory-efficient short read aligner.}},
year = {2009}
}

@article{Deluca2012,
abstract = {Summary: RNA-seq, the application of next-generation sequencing to RNA, provides transcriptome-wide characterization of cellular activity. Assessment of sequencing performance and library quality is critical to the interpretation of RNA-seq data, yet few tools exist to address this issue. We introduce RNA-SeQC, a program which provides key measures of data quality. These metrics include yield, alignment and duplication rates; GC bias, rRNA content, regions of alignment (exon, intron and intragenic), continuity of coverage, 3′/5′ bias and count of detectable transcripts, among others. The software provides multi-sample evaluation of library construction protocols, input materials and other experimental parameters. The modularity of the software enables pipeline integration and the routine monitoring of key measures of data quality such as the number of alignable reads, duplication rates and rRNA contamination. RNA-SeQC allows investigators to make informed decisions about sample inclusion in downstream analysis. In summary, RNA-SeQC provides quality control measures critical to experiment design, process optimization and downstream computational analysis.$\backslash$nAvailability and implementation: See www.genepattern.org to run online, or www.broadinstitute.org/rna-seqc/ for a command line tool.$\backslash$nContact: ddeluca@broadinstitute.org$\backslash$nSupplementary information: Supplementary data are available at Bioinformatics online.},
author = {Deluca, David S. and Levin, Joshua Z. and Sivachenko, Andrey and Fennell, Timothy and Nazaire, Marc Danie and Williams, Chris and Reich, Michael and Winckler, Wendy and Getz, Gad},
doi = {10.1093/bioinformatics/bts196},
isbn = {1367-4811 (Electronic)$\backslash$r1367-4803 (Linking)},
issn = {13674803},
journal = {Bioinformatics},
mendeley-groups = {AllelicSeries},
number = {11},
pages = {1530--1532},
pmid = {22539670},
title = {{RNA-SeQC: RNA-seq metrics for quality control and process optimization}},
volume = {28},
year = {2012}
}

@misc{Andrews2010,
abstract = {FastQC aims to provide a simple way to do some quality control checks on raw sequence data coming from high throughput sequencing pipelines. It provides a modular set of analyses which you can use to give a quick impression of whether your data has any problems of which you should be aware before doing any further analysis. The main functions of FastQC are Import of data from BAM, SAM or FastQ files (any variant) Providing a quick overview to tell you in which areas there may be problems Summary graphs and tables to quickly assess your data Export of results to an HTML based permanent report Offline operation to allow automated generation of reports without running the interactive application},
author = {Andrews, S.},
booktitle = {Bioinformatics},
doi = {citeulike-article-id:11583827},
mendeley-groups = {AllelicSeries},
pages = {1},
title = {{FastQC: A quality control tool for high throughput sequence data}},
year = {2010}
}

@article{Bray2016,
abstract = {We present kallisto, an RNA-seq quantification program that is two orders of magnitude faster than previous approaches and achieves similar accuracy. Kallisto pseudoaligns reads to a reference, producing a list of transcripts that are compatible with each read while avoiding alignment of individual bases. We use kallisto to analyze 30 million unaligned paired-end RNA-seq reads in {\textless}10 min on a standard laptop computer. This removes a major computational bottleneck in RNA-seq analysis.},
archivePrefix = {arXiv},
arxivId = {1505.02710},
author = {Bray, Nicolas L and Pimentel, Harold J and Melsted, P{\'{a}}ll and Pachter, Lior},
doi = {10.1038/nbt.3519},
isbn = {1087-0156$\backslash$r1546-1696},
issn = {1546-1696},
journal = {Nature biotechnology},
keywords = {1,2,3 and lior pachter,4,bray 1,department of computer science,harold pimentel,innovative genomics initiative,nicolas l,p{\'{a}}ll melsted,r-optimal rna-seq quantification,uc berkeley},
mendeley-groups = {PastPapers/Fog2Aging,PastPapers/MPRSQ,AllelicSeries},
number = {5},
pages = {525--7},
pmid = {27043002},
title = {{Near-optimal probabilistic RNA-seq quantification.}},
volume = {34},
year = {2016}
}

@article{Pimentel2016a,
abstract = {We describe sleuth (http://pachterlab.github.io/sleuth), a method for the differential analysis of gene expression data that utilizes bootstrapping in conjunction with response error linear modeling to decouple biological variance from inferential variance. sleuth is implemented in an interactive shiny app that utilizes kallisto quantifications and bootstraps for fast and accurate analysis of data from rna-seq experiments. Many methods have been developed for differential analysis of RNA-seq data 1 . Some of these methods are designed to translate models developed for microarray analysis 2 , while others are based on models tailored to RNA-seq 1,3–5 . Differential analysis of RNA-seq experiments requires careful assessment of gene expression variability from a few replicate samples to identify biologically relevant expression differences between conditions 6 . There is ongoing debate on even basic questions such as how to measure gene abundances 1 , whether there is sufficient power to test for differences in abundance of individual isoforms 7 , and how to best utilize biological replicates 1 . Part of the reason for this uncertainty is the lack of agreed-upon standards for testing and benchmark-ing RNA-seq methods. In most cases, accuracy claims are based on simulations of read counts from distributions assumed in the models, rather than on simulations of raw reads 2,5,6,8,9 . Such read-count-based simulations typically discount the effects of ambigu-ously mapping reads and fail to capture both the possibilities for and challenges of isoform-specific differential analysis. Here we describe a novel approach to RNA-seq differential analysis and a comprehensive benchmarking framework with broader scale and scope than have previously been published. Our approach is implemented along with interactive visualization software that provides crucial transparency in assessing results, and it offers users a convenient tool for exploratory data analysis. Throughout the paper we use the name 'sleuth' to refer to both our statistical method and the software application. sleuth relies on variance decomposition to identify biologi-cal differences in transcript or gene expression (Fig. 1). While using a standard strategy of shrinkage to stabilize variance estimates from few samples 2,6 , sleuth is able to leverage recent advances in quantification 10 to obtain error estimates that can be used to decouple biological variance from inferential vari-ance before shrinkage (Fig. 1a). Variance decomposition is important because of the diversity of variance estimates across genes that arise when quantifying abundances. In one example (Fig. 1b,c), DESeq2 and voom were run on the same data with featureCounts summaries, and these tools identified a gene as differentially expressed at a false discovery rate (FDR) thresh-old of 0.10 (reported FDR 8.81 × 10 −21 and 5.56 × 10 −10 , respec-tively); whereas sleuth did not find differences between conditions to be significant (reported FDR 0.156) because of the high infer-ential variance. Some methods have attempted to utilize estimates of quantification errors 6,11,12 , but these methods are limited by long run times and lack of robustness to ambiguously mapping reads. By leveraging kallisto's 10 rapid quantification and variance estimation, sleuth overcomes these issues and provides a statistically rigorous, flexible, and efficient tool for RNA-seq analysis. To test its performance, we compared sleuth with other widely used methods on both simulated and biological data. Our simu-lation was based on two experimental conditions with three replicates each (see Online Methods). We simulated biological variance (dispersion) according to the negative binomial count model used by DESeq2 (ref. 9). To accurately assess perform-ance, each simulation was repeated 20 times. All programs except sleuth used quantifications inferred from genome alignments (see Online Methods). Full details of the simulation experiments are in Supplementary Note 1. sleuth displayed higher sensitivity than Cuffdiff 2 (ref. 12), DESeq 6 , DESeq2 (ref. 9), EBSeq 7 , edgeR 8 , voom 2 ; and sleuth dis-played log-fold change 13 in the FDR range of usual interest (0–10{\%}) and beyond, up to FDR 0.3 (Fig. 2; Supplementary Figs. 1 and 2; and Supplementary Note 1). As expected, our simulations found that DESeq2 has more power than DESeq at all relevant FDRs, and that the na{\"{i}}ve ranking of genes by log-fold change produces poor results. To control for the effect of different filtering strategies, we ran all programs on a common filtered set of genes and showed that sleuth maintains its sensitivity advantage (Supplementary Note 1). Finally, to show the benefit of directly estimating infer-ential variance, we also demonstrated that sleuth outperforms models in which inferential variance is assumed to be Poisson or zero (Supplementary Note 1). Since FDR control is fundamental for identifying differentially expressed genes in experiments with few replicates, we carefully},
author = {Pimentel, Harold and Bray, Nicolas L and Puente, Suzette and Melsted, P{\'{a}}ll and Pachter, Lior},
doi = {10.1038/nMeth.4324},
file = {:Users/dangeles/Documents/Mendeley Desktop/Pimentel et al. - 2017 - differential analysis of rna-seq incorporating quantification uncertainty.pdf:pdf},
journal = {brief communications nature methods},
mendeley-groups = {AllelicSeries,PastPapers/MPRSQ,PastPapers/Fog2Aging},
number = {7},
title = {{Differential analysis of RNA-seq incorporating quantification uncertainty}},
volume = {14},
year = {2017}
}

@article{Rossum2011a,
abstract = {Python is a programming language that lets you work more quickly and integrate your systems more effectively. You can learn to use Python and see almost immediate gains in productivity and lower maintenance costs.},
author = {Rossum, Guido Van and Foundation, Python Software and Swallow, Unladen and Python, Stackless and Software, Python and License, Foundation},
isbn = {978-1-56592-265-5},
journal = {Flying},
mendeley-groups = {AllelicSeries},
pages = {1--14},
title = {{Python ( programming language )}},
year = {2011}
}
@article{Waskom,
abstract = {This is a major release from 0.6. The main new feature is swarmplot which implements the beeswarm approach for drawing categorical scatterplots. There are also some performance improvements, bug fixes, and updates for compatibility with new versions of dependencies.$\backslash$n$\backslash$n$\backslash$n  Added the swarmplot function, which draws beeswarm plots. These are$\backslash$ncategorical scatterplots, similar to those produced by stripplot,$\backslash$nbut position of the points on the categorical axis is chosen to$\backslash$navoid overlapping points. See the$\backslash$ncategorical plot tutorial for more$\backslash$ninformation.$\backslash$n  Added an additional rule when determining category order in$\backslash$ncategorical plots. Now, when numeric variables are used in a$\backslash$ncategorical role, the default behavior is to sort the unique levels$\backslash$nof the variable (i.e they will be in proper numerical order). This$\backslash$ncan still be overridden by the appropriate {\{}*{\_}{\}}order parameter,$\backslash$nand variables with a category datatype will still follow the$\backslash$ncategory order even if the levels are strictly numerical.$\backslash$n  Changed some of the stripplot defaults to be closer to swarmplot.$\backslash$nPoints are somewhat smaller, have no outlines, and are not split by$\backslash$ndefault when using hue.$\backslash$n  Changed how stripplot draws points when using hue nesting with$\backslash$nsplit=False so that the different hue levels are not drawn$\backslash$nstrictly on top of each other.$\backslash$n  Improve performance for large dendrograms in clustermap.$\backslash$n  Added font.size to the plotting context definition so that the$\backslash$ndefault output from plt.text will be scaled appropriately.$\backslash$n  Fixed a bug in clustermap when fastcluster is not installed.$\backslash$n  Fixed a bug in the zscore calculation in clustermap.$\backslash$n  Fixed a bug in distplot where sometimes the default number of bins$\backslash$nwould not be an integer.$\backslash$n  Fixed a bug in stripplot where a legend item would not appear for a$\backslash$nhue level if there were no observations in the first group of$\backslash$npoints.$\backslash$n  Heatmap colorbars are now rasterized for better performance in$\backslash$nvector plots.$\backslash$n  Added workarounds for some matplotlib boxplot issues, such as$\backslash$nstrange colors of outlier points.$\backslash$n  Added workarounds for an issue where violinplot edges would be$\backslash$nmissing or have random colors.$\backslash$n  Added a workaround for an issue where only one heatmap cell would be$\backslash$nannotated on some matplotlib backends.$\backslash$n  Fixed a bug on newer versions of matplotlib where a colormap would$\backslash$nbe erroneously applied to scatterplots with only three observations.$\backslash$n  Updated seaborn for compatibility with matplotlib 1.5.$\backslash$n  Added compatibility for various IPython (and Jupyter) versions in$\backslash$nfunctions that use widgets.},
author = {Waskom, Michael and St-Jean, Samuel and Evans, Constantine and Warmenhoven, Jordi and Meyer, Kyle and Martin, Marcel and Rocher, Luc and Hobson, Paul and Bachant, Pete and Nagy, Tamas and Wehner, Daniel and Botvinnik, Olga and Megies, Tobias and Lukauskas, Saulius and Drewokane and Ziegler, Erik and Yarkoni, Tal and Miles, Alistair and Lee, Antony and Coelho, Luis Pedro and Halchenko, Yaroslav and Augspurger, Tom and Hitz, Gregory and Vanderplas, Jake and Fitzgerald, Clark and Cole, John B. and Gkunter and Villalba, Santi and Hoyer, Stephan and Quintero, Eric},
doi = {10.5281/zenodo.45133},
keywords = {Seaborn},
mendeley-groups = {PastPapers/MPRSQ,PastPapers/Fog2Aging,PastPapers/PEA,AllelicSeries},
mendeley-tags = {Seaborn},
title = {{seaborn: v0.7.0 (January 2016)}},
year = {2016}
}
@article{McKinney2011,
abstract = {In this paper we will discuss pandas, a Python library of rich data structures and tools for working with structured data sets common to statistics, ﬁnance, social sciences, and many other ﬁelds. The library provides integrated, intuitive routines for performing common data manipulations and analysis on such data sets. It aims to be the foundational layer for the future of statistical computing in Python. It serves as a strong complement to the existing scientiﬁc Python stack while implementing and improving upon the kinds of data manipulation tools found in other statistical programming languages such as R. In addition to detailing its design and features of pandas, we will discuss future avenues of work and growth opportunities for statistics and data analysis applications in the Python language.},
author = {McKinney, Wes},
journal = {Python for High Performance and Scientific Computing},
mendeley-groups = {PastPapers/Tissue Enrichment Analysis,PastPapers/MPRSQ,PastPapers/Fog2Aging,PastPapers/PEA,AllelicSeries},
pages = {1--9},
title = {{pandas: a Foundational Python Library for Data Analysis and Statistics}},
year = {2011}
}
@article{Salvatier2015,
abstract = {Probabilistic programming (PP) allows flexible specification of Bayesian statistical models in code. PyMC3 is a new, open-source PP framework with an intutive and readable, yet powerful, syntax that is close to the natural syntax statisticians use to describe models. It features next-generation Markov chain Monte Carlo (MCMC) sampling algorithms such as the No-U-Turn Sampler (NUTS; Hoffman, 2014), a self-tuning variant of Hamiltonian Monte Carlo (HMC; Duane, 1987). Probabilistic programming in Python confers a number of advantages including multi-platform compatibility, an expressive yet clean and readable syntax, easy integration with other scientific libraries, and extensibility via C, C++, Fortran or Cython. These features make it relatively straightforward to write and use custom statistical distributions, samplers and transformation functions, as required by Bayesian analysis.},
archivePrefix = {arXiv},
arxivId = {1507.08050},
author = {Salvatier, John and Wiecki, Thomas and Fonnesbeck, Christopher},
doi = {10.7717/peerj-cs.55},
eprint = {1507.08050},
file = {:Users/dangeles/Documents/Mendeley Desktop/Salvatier, Wiecki, Fonnesbeck - 2015 - Probabilistic Programming in Python using PyMC.pdf:pdf},
isbn = {9783319238258},
issn = {2376-5992},
journal = {PeerJ Computer Science},
keywords = {bayesian statistic,markov chain monte carlo,probabilistic programming,python,statistical modeling},
mendeley-groups = {PastPapers/MPRSQ,PastPapers/Fog2Aging,AllelicSeries},
number = {e55},
pages = {1--24},
title = {{Probabilistic Programming in Python using PyMC}},
volume = {2},
year = {2015}
}

@article{Oliphant2007,
abstract = {By itself, Python is an excellent "steering" language for scientific codes written in other languages. However, with additional basic tools, Python transforms into a high-level language suited for scientific and engineering code that's often fast enough to be immediately useful but also flexible enough to be sped up with additional extensions.},
author = {Oliphant, Travis E},
doi = {10.1109/MCSE.2007.58},
isbn = {9781584889298},
issn = {1521-9615},
journal = {Computing in Science and Engineering},
mendeley-groups = {PastPapers/MPRSQ,AllelicSeries},
pages = {10--20},
title = {{SciPy: Open source scientific tools for Python}},
volume = {9},
year = {2007}
}

@article{Perez2007,
abstract = {T he backbone of scientific computing is mostly a collection of high-perfor-mance code written in Fortran, C, and C++ that typically runs in batch mode on large systems, clusters, and supercomputers. However, over the past decade, high-level environ-ments that integrate easy-to-use interpreted lan-guages, comprehensive numerical libraries, and visualization facilities have become extremely popu-lar in this field. As hardware becomes faster, the crit-ical bottleneck in scientific computing isn't always the computer's processing time; the scientist's time is also a consideration. For this reason, systems that allow rapid algorithmic exploration, data analysis, and vi-sualization have become a staple of daily scientific work. The Interactive Data Language (IDL) and Matlab (for numerical work), and Mathematica and Maple (for work that includes symbolic manipula-tion) are well-known commercial environments of this kind. GNU Data Language, Octave, Maxima and Sage provide their open source counterparts. All these systems offer an interactive command line in which code can be run immediately, without having to go through the traditional edit/com-pile/execute cycle. This flexible style matches well the spirit of computing in a scientific context, in which determining what computations must be performed next often requires significant work. An interactive environment lets scientists look at data, test new ideas, combine algorithmic approaches, and evaluate their outcome directly. This process might lead to a final result, or it might clarify how they need to build a more static, large-scale pro-duction code. As this article shows, Python (www.python.org) is an excellent tool for such a workflow. 1 The IPython project (http://ipython.scipy.org) aims to not only provide a greatly enhanced Python shell but also facilities for interactive distributed and par-allel computing, as well as a comprehensive set of tools for building special-purpose interactive envi-ronments for scientific computing.},
author = {P{\'{e}}rez, F. and Granger, B.E.},
doi = {doi:10.1109/MCSE.2007.53.},
file = {:Users/dangeles/Documents/Mendeley Desktop/P{\'{e}}rez, Granger - 2007 - IPython A System for Interactive Scientific Computing Python An Open and General- Purpose Environment.pdf:pdf},
isbn = {3518437208},
issn = {15219615},
journal = {Computing in Science and Engineering},
mendeley-groups = {PastPapers/MPRSQ,PastPapers/Fog2Aging,PastPapers/PEA,AllelicSeries},
number = {3},
pages = {21--29},
pmid = {1000224768},
title = {{IPython: A System for Interactive Scientific Computing Python: An Open and General- Purpose Environment}},
volume = {9},
year = {2007}
}

@article{Pedregosa2012a,
abstract = {Scikit-learn is a Python module integrating a wide range of state-of-the-art machine learning algorithms for medium-scale supervised and unsupervised problems. This package focuses on bringing machine learning to non-specialists using a general-purpose high-level language. Emphasis is put on ease of use, performance, documentation, and API consistency. It has minimal dependencies and is distributed under the simplified BSD license, encouraging its use in both academic and commercial settings. Source code, binaries, and documentation can be downloaded from http://scikit-learn.sourceforge.net.},
archivePrefix = {arXiv},
arxivId = {1201.0490},
author = {Pedregosa, Fabian and Varoquaux, Ga{\"{e}}l and Gramfort, Alexandre and Michel, Vincent and Thirion, Bertrand and Grisel, Olivier and Blondel, Mathieu and Prettenhofer, Peter and Weiss, Ron and Dubourg, Vincent and Vanderplas, Jake and Passos, Alexandre and Cournapeau, David and Brucher, Matthieu and Perrot, Matthieu and Duchesnay, {\'{E}}douard},
doi = {10.1007/s13398-014-0173-7.2},
eprint = {1201.0490},
isbn = {1532-4435},
issn = {15324435},
journal = {Journal of Machine Learning Research},
mendeley-groups = {PastPapers/MPRSQ,AllelicSeries},
pages = {2825--2830},
pmid = {1000044560},
title = {{Scikit-learn: Machine Learning in Python}},
volume = {12},
year = {2012}
}

@article{Pedregosa2012b,
abstract = {Scikit-learn is a Python module integrating a wide range of state-of-the-art machine learning algorithms for medium-scale supervised and unsupervised problems. This package focuses on bringing machine learning to non-specialists using a general-purpose high-level language. Emphasis is put on ease of use, performance, documentation, and API consistency. It has minimal dependencies and is distributed under the simplified BSD license, encouraging its use in both academic and commercial settings. Source code, binaries, and documentation can be downloaded from http://scikit-learn.sourceforge.net.},
archivePrefix = {arXiv},
arxivId = {1201.0490},
author = {Pedregosa, Fabian and Varoquaux, Ga{\"{e}}l and Gramfort, Alexandre and Michel, Vincent and Thirion, Bertrand and Grisel, Olivier and Blondel, Mathieu and Prettenhofer, Peter and Weiss, Ron and Dubourg, Vincent and Vanderplas, Jake and Passos, Alexandre and Cournapeau, David and Brucher, Matthieu and Perrot, Matthieu and Duchesnay, {\'{E}}douard},
doi = {10.1007/s13398-014-0173-7.2},
eprint = {1201.0490},
isbn = {1532-4435},
issn = {15324435},
journal = {Journal of Machine Learning Research},
mendeley-groups = {AllelicSeries},
pages = {2825--2830},
pmid = {1000044560},
title = {{Scikit-learn: Machine Learning in Python}},
volume = {12},
year = {2012}
}

@article{Hagberg2008,
abstract = {NetworkX is a Python language package for exploration and analysis of networks and network algorithms. The core package provides data structures for representing many types of networks, or graphs, including simple graphs, directed graphs, and graphs with parallel edges and self-loops. The nodes in NetworkX graphs can be any (hashable) Python object and edges can contain arbitrary data; this flexibility makes NetworkX ideal for representing networks found in many different scientific fields. In addition to the basic data structures many graph algorithms are implemented for calculating network properties and structure measures: shortest paths, betweenness centrality, clustering, and degree distribution and many more. NetworkX can read and write various graph formats for easy exchange with existing data, and provides generators for many classic graphs and popular graph models, such as the Erdos-Renyi, Small World, and Barabasi-Albert models. The ease-of-use and flexibility of the Python programming language together with connection to the SciPy tools make NetworkX a powerful tool for scientific computations. We discuss some of our recent work studying synchronization of coupled oscillators to demonstrate how NetworkX enables research in the field of computational networks.},
author = {Hagberg, Aric A. and Schult, Daniel A. and Swart, Pieter J.},
file = {:Users/dangeles/Documents/Mendeley Desktop/Hagberg, Schult, Swart - 2008 - Exploring network structure, dynamics, and function using NetworkX.pdf:pdf},
isbn = {3333333333},
issn = {1540-9295},
journal = {Proceedings of the 7th Python in Science Conference (SciPy 2008)},
mendeley-groups = {PastPapers/MPRSQ,AllelicSeries},
number = {SciPy},
pages = {11--15},
title = {{Exploring network structure, dynamics, and function using NetworkX}},
year = {2008}
}
@article{VanDerWalt2011,
abstract = {In the Python world, NumPy arrays are the standard representation for numerical data and enable efficient implementation of numerical computations in a high-level language. As this effort shows, NumPy performance can be improved through three techniques: vectorizing calculations, avoiding copying data in memory, and minimizing operation counts.},
archivePrefix = {arXiv},
arxivId = {1102.1523},
author = {{Van Der Walt}, St{\'{e}}fan and Colbert, S. Chris and Varoquaux, Ga{\"{e}}l},
doi = {10.1109/MCSE.2011.37},
isbn = {1521-9615 VO - 13},
issn = {15219615},
journal = {Computing in Science and Engineering},
keywords = {NumPy,Python,numerical computations,programming libraries,scientific programming},
mendeley-groups = {PastPapers/Tissue Enrichment Analysis,PastPapers/MPRSQ,PastPapers/Fog2Aging,PastPapers/PEA,AllelicSeries},
number = {2},
pages = {22--30},
pmid = {1000224770},
title = {{The NumPy array: A structure for efficient numerical computation}},
volume = {13},
year = {2011}
}
@article{Hunter2007,
abstract = {Matplotlib is a 2D graphics package used for Python for application development, interactive scripting, and publication-quality image generation across user interfaces and operating systems.},
archivePrefix = {arXiv},
arxivId = {arXiv:cond-mat/0402594v3},
author = {Hunter, John D.},
doi = {10.1109/MCSE.2007.55},
isbn = {1521-9615 VO - 9},
issn = {15219615},
journal = {Computing in Science and Engineering},
mendeley-groups = {PastPapers/Fog2Aging,PastPapers/MPRSQ,PastPapers/PEA,AllelicSeries},
number = {3},
pages = {99--104},
pmid = {1000044628},
primaryClass = {arXiv:cond-mat},
title = {{Matplotlib: A 2D graphics environment}},
volume = {9},
year = {2007}
}
@article{Allen2015,
abstract = {The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator - a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.},
author = {Allen, Benjamin L and Taatjes, Dylan J},
doi = {10.1038/nrm3951},
isbn = {1471-0080 (Electronic)$\backslash$r1471-0072 (Linking)},
issn = {1471-0080},
journal = {Nature reviews. Molecular cell biology},
keywords = {c u s o,n t r a,nsc},
mendeley-groups = {AllelicSeries},
number = {3},
pages = {155--166},
pmid = {25693131},
title = {{The Mediator complex: a central integrator of transcription.}},
volume = {16},
year = {2015}
}
@article{Moghal2003a,
abstract = {Negative regulation of receptor tyrosine kinase (RTK)/RAS signaling pathways is important for normal development and the prevention of disease in humans. We have used a genetic screen in \emph{C.~elegans} to identify genes that antagonize the activity of activated LET-23, a member of the EGFR family of RTKs. We identified two loss-of-function mutations in dpy-22, previously cloned as sop-1, that promote the ability of activated LET-23 to induce ectopic vulval fates. DPY-22 is a glutamine-rich protein that is most similar to human TRAP230, a component of a transcriptional mediator complex. DPY-22 has previously been shown to regulate WNT responses through inhibition of the beta-catenin-like protein BAR-1. We provide evidence that DPY-22 also inhibits RAS-dependent vulval fate specification independently of BAR-1, and probably regulates the activities of multiple transcription factors during development. Furthermore, we demonstrate that although inhibition of BAR-1-dependent gene expression has been shown to require the C-terminal glutamine-rich region, this region is dispensable for inhibition of RAS-dependent cell differentiation. Thus, the glutamine-rich region contributes to specificity of this class of mediator protein.},
author = {Moghal, N. and Sternberg, Paul W.},
doi = {10.1242/dev.00189},
isbn = {0950-1991 (Print)$\backslash$r0950-1991 (Linking)},
issn = {09501991},
journal = {Development},
keywords = {dpy-22,egf,let-23,mediator,ras,sop-1,vulva},
mendeley-groups = {AllelicSeries},
number = {1},
pages = {57--69},
pmid = {12441291},
title = {{A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in \emph{C.~elegans}.}},
volume = {130},
year = {2003}
}
@article{Takagi2006,
abstract = {Others have shown that yeast strains bearing a ts mutation in the Srb4 subunit of Mediator cease transcription of all mRNA at the restrictive temperature, in a manner virtually indistinguishable from a strain bearing a ts mutation in the largest subunit of RNA polymerase II. We find that srb4ts Mediator is defective for the stimulation of basal RNA polymerase II transcription at the restrictive temperature in vitro. Taken together, these findings lead to the suggestion that Mediator is required for basal RNA polymerase II transcription in vivo. On this basis, Mediator is identified as a general transcription factor, comparable in importance to RNA polymerase II and other general factors for the initiation of transcription. The possibility that Mediator serves as an anti-inhibitor, opposing the effects of global negative regulators, is largely excluded.},
author = {Takagi, Yuichiro and Kornberg, Roger D},
doi = {10.1074/jbc.M508253200},
issn = {0021-9258},
journal = {The Journal of biological chemistry},
mendeley-groups = {AllelicSeries},
month = {jan},
number = {1},
pages = {80--9},
pmid = {16263706},
title = {{Mediator as a general transcription factor.}},
volume = {281},
year = {2006}
}
@article{Knuesel2009,
abstract = {The human CDK8 subcomplex (CDK8, cyclin C, Med12, and Med13) negatively regulates transcription in ways not completely defined; past studies suggested CDK8 kinase activity was required for its repressive function. Using a reconstituted transcription system together with recombinant or endogenous CDK8 subcomplexes, we demonstrate that, in fact, Med12 and Med13 are critical for subcomplex-dependent repression, whereas CDK8 kinase activity is not. A hallmark of activated transcription is efficient reinitiation from promoter-bound scaffold complexes that recruit a series of pol II enzymes to the gene. Notably, the CDK8 submodule strongly represses even reinitiation events, suggesting a means to fine tune transcript levels. Structural and biochemical studies confirm the CDK8 submodule binds the Mediator leg/tail domain via the Med13 subunit, and this submodule-Mediator association precludes pol II recruitment. Collectively, these results reveal the CDK8 subcomplex functions as a simple switch that controls the Mediator-pol II interaction to help regulate transcription initiation and reinitiation events. As Mediator is generally required for expression of protein-coding genes, this may reflect a common mechanism by which activated transcription is shut down in human cells.},
author = {Knuesel, Matthew T and Meyer, Krista D and Bernecky, Carrie and Taatjes, Dylan J},
doi = {10.1101/gad.1767009},
file = {:Users/dangeles/Documents/Mendeley Desktop/Knuesel et al. - 2009 - The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function.pdf:pdf},
issn = {1549-5477},
journal = {Genes {\&} development},
mendeley-groups = {AllelicSeries},
month = {Feb},
number = {4},
pages = {439--51},
pmid = {19240132},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function.}},
volume = {23},
year = {2009}
}
@article{Elmlund2006,
abstract = {CDK8 (cyclin-dependent kinase 8), along with CycC, Med12, and Med13, form a repressive module (the Cdk8 module) that prevents RNA polymerase II (pol II) interactions with Mediator. Here, we report that the ability of the Cdk8 module to prevent pol II interactions is independent of the Cdk8-dependent kinase activity. We use electron microscopy and single-particle reconstruction to demonstrate that the Cdk8 module forms a distinct structural entity that binds to the head and middle region of Mediator, thereby sterically blocking interactions with pol II.},
author = {Elmlund, Hans and Baraznenok, Vera and Lindahl, Martin and Samuelsen, Camilla O and Koeck, Philip J B and Holmberg, Steen and Hebert, Hans and Gustafsson, Claes M},
doi = {10.1073/pnas.0607483103},
file = {:Users/dangeles/Documents/Mendeley Desktop/Elmlund et al. - 2006 - The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II.pdf:pdf},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
mendeley-groups = {AllelicSeries},
month = {oct},
number = {43},
pages = {15788--93},
pmid = {17043218},
publisher = {National Academy of Sciences},
title = {{The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II.}},
volume = {103},
year = {2006}
}
@article{Grants2015,
abstract = {The Mediator multiprotein complex ('Mediator') is an important transcriptional coregulator that is evolutionarily conserved throughout eukaryotes. Although some Mediator subunits are essential for the transcription of all protein-coding genes, others influence the expression of only subsets of genes and participate selectively in cellular signaling pathways. Here, we review the current knowledge of Mediator subunit function in the nematode \emph{Caenorhabditis~elegans}, a metazoan in which established and emerging genetic technologies facilitate the study of developmental and physiological regulation in vivo. In this nematode, unbiased genetic screens have revealed critical roles for Mediator components in core developmental pathways such as epidermal growth factor (EGF) and Wnt/$\beta$-catenin signaling. More recently, important roles for \emph{C.~elegans} Mediator subunits have emerged in the regulation of lipid metabolism and of systemic stress responses, engaging conserved transcription factors such as nuclear hormone receptors (NHRs). We emphasize instances where similar functions for individual Mediator subunits exist in mammals, highlighting parallels between Mediator subunit action in nematode development and in human cancer biology. We also discuss a parallel between the association of the Mediator subunit MED12 with several human disorders and the role of its \emph{C.~elegans} ortholog mdt-12 as a regulatory hub that interacts with numerous signaling pathways.},
author = {Grants, Jennifer M and Goh, Grace Y S and Taubert, Stefan},
doi = {10.1093/nar/gkv037},
file = {:Users/dangeles/Documents/Mendeley Desktop/Grants, Goh, Taubert - 2015 - The Mediator complex of \emph{Caenorhabditis~elegans} insights into the developmental and physiological roles of.pdf:pdf},
issn = {1362-4962},
journal = {Nucleic acids research},
mendeley-groups = {AllelicSeries},
month = {Feb},
number = {4},
pages = {2442--53},
pmid = {25634893},
publisher = {Oxford University Press},
title = {{The Mediator complex of \emph{Caenorhabditis~elegans}: insights into the developmental and physiological roles of a conserved transcriptional coregulator.}},
volume = {43},
year = {2015}
}

@article{Zhang2000,
abstract = {Over half of the neurons in \emph{Caenorhabditis~elegans} send axons to the nerve ring, a large neuropil in the head of the animal. Genetic screens in animals that express the green fluorescent protein in a subset of sensory neurons identified eight new sax genes that affect the morphology of nerve ring axons. sax-3/robo mutations disrupt axon guidance in the nerve ring, while sax-5, sax-9 and unc-44 disrupt both axon guidance and axon extension. Axon extension and guidance proceed normally in sax-1, sax-2, sax-6, sax-7 and sax-8 mutants, but these animals exhibit later defects in the maintenance of nerve ring structure. The functions of existing guidance genes in nerve ring development were also examined, revealing that SAX-3/Robo acts in parallel to the VAB-1/Eph receptor and the UNC-6/netrin, UNC-40/DCC guidance systems for ventral guidance of axons in the amphid commissure, a major route of axon entry into the nerve ring. In addition, SAX-3/Robo and the VAB-1/Eph receptor both function to prevent aberrant axon crossing at the ventral midline. Together, these genes define pathways required for axon growth, guidance and maintenance during nervous system development.},
author = {Zhang, H. and Emmons, S. W.},
doi = {10.1101/gad.814700},
isbn = {0950-1991 (Print)$\backslash$n0950-1991 (Linking)},
issn = {08909369},
journal = {Genes and Development},
keywords = {Cell fate,Development,Homeobox gene,Regulation,Transcription},
mendeley-groups = {AllelicSeries},
number = {17},
pages = {2161--2172},
pmid = {10409513},
title = {{A \emph{C.~elegans} mediator protein confers regulatory selectivity on lineage-specific expression of a transcription factor gene}},
volume = {14},
year = {2000}
}
@misc{Bourbon2004,
author = {Bourbon, Henri-Marc and Aguilera, Andres and Ansari, Aseem Z. and Asturias, Francisco J. and Berk, Arnold J. and Bjorklund, Stefan and Blackwell, T.Keith and Borggrefe, Tilman and Carey, Michael and Carlson, Marian and Conaway, Joan W. and Conaway, Ronald C. and Emmons, Scott W. and Fondell, Joseph D. and Freedman, Leonard P. and Fukasawa, Toshio and Gustafsson, Claes M. and Han, Min and He, Xi and Herman, Paul K. and Hinnebusch, Alan G. and Holmberg, Steen and Holstege, Frank C. and Jaehning, Judith A. and Kim, Young-Joon and Kuras, Laurent and Leutz, Achim and Lis, John T. and Meisterernest, Michael and Naar, Anders M. and Nasmyth, Kim and Parvin, Jeffrey D. and Ptashne, Mark and Reinberg, Danny and Ronne, Hans and Sadowski, Ivan and Sakurai, Hiroshi and Sipiczki, Matthias and Sternberg, Paul W. and Stillman, David J. and Strich, Randy and Struhl, Kevin and Svejstrup, Jasper Q. and Tuck, Simon and Winston, Fred and Roeder, Robert G. and Kornberg, Roger D.},
booktitle = {Molecular Cell},
doi = {10.1016/j.molcel.2004.05.011},
issn = {10972765},
mendeley-groups = {AllelicSeries},
number = {5},
pages = {553--557},
title = {{A Unified Nomenclature for Protein Subunits of Mediator Complexes Linking Transcriptional Regulators to RNA Polymerase II}},
volume = {14},
year = {2004}
}
@article{Aroian1990,
author = {Aroian, Raffi V. and Koga, Makoto and Mendel, Jane E. and Ohshima, Yasumi and Sternberg, Paul W.},
doi = {10.1038/348693a0},
issn = {0028-0836},
journal = {Nature},
month = {dec},
number = {6303},
pages = {693--699},
publisher = {Nature Publishing Group},
title = {{The let-23 gene necessary for  \emph{Caenorhabditis~elegans} vulval induction encodes a tyrosine kinase of the EGF receptor subfamily}},
volume = {348},
year = {1990}
}
@article{Han1991,
abstract = {The let-60 gene of  \emph{Caenorhabditis~elegans} controls the choice between vulval and hypodermal differentiation in response to an inductive signal from the gonad. let-60 encodes a ras protein that acts downstream of the let-23 receptor tyrosine kinase in a signal transduction pathway. Dominant-negative mutations of let-60 [let-60(dn)] cause a reduction of the gene activity in let-60(dn)/+ heterozygotes and a vulva-less mutant phenotype. We have found that nine let-60(dn) mutations cause replacements of conserved residues. Four are in two novel positions; others are in positions known previously to cause dominant-negative mutations in mammalian cells. The locations of these lesions suggest that they disrupt the ability of the ras protein to bind guanine nucleotides. Four let-60(dn) mutant genes were introduced into wild-type animals in the form of extrachromosomal arrays and were found to generate three dominant phenotypes--lethality, vulva-less, or multivulva--depending on gene dose and alleles. The dominant lethality caused by high-dose transgenic let-60(dn) genes suggests a toxic effect of these mutant genes in early development. The dominant-negative effects of these mutations in heterozygotes are likely to be caused by competition between let-60(dn) and let-60(+) protein for a positive regulator. All let-60(dn) mutations interfere with let-60(+) activity, but some alleles have partial constitutive activity, suggesting that the ability to interact with the activator is separable from the ability to exert a physiological effect (stimulation of vulval differentiation). These dn mutations might be useful for interfering with ras-mediated signal transduction pathways in other multicellular organisms.},
author = {Han, M. and Sternberg, P. W.},
doi = {10.1101/gad.5.12a.2188},
isbn = {0890-9369},
issn = {08909369},
journal = {Genes and Development},
keywords = {1991,2,Animals,Arginine,Arginine: chemistry,Asparagine,Asparagine: chemistry,Caenorhabditis,Caenorhabditis elegans Proteins,Caenorhabditis: genetics,Cell Differentiation,Cell Differentiation: genetics,Codon,Dominant,Female,Gene Expression Regulation,Genes,Genetically Modified,Genotype,Guanine Nucleotides,Guanine Nucleotides: metabolism,Helminth Proteins,Helminth Proteins: genetics,Mutation,Phenotype,Vulva,Vulva: cytology,caenorhabditis elegans,dominant-negative mutations,each of six vulval,hermaphrodites,in  \emph{Caenorhabditis~elegans}  ,precursor cells,prior to vulval differentiation,ras,ras Proteins,received july 30,revised version accepted september,vpcs,vulval induction},
number = {12 A},
pages = {2188--2198},
pmid = {1748278},
title = {{Analysis of dominant-negative mutations of the  \emph{Caenorhabditis~elegans} let- 60 ras gene}},
volume = {5},
year = {1991}
}
@article{Clark1994,
abstract = {The  \emph{Caenorhabditis~elegans} locus lin-15 negatively regulates an intercellular signaling process that induces formation of the hermaphrodite vulva. The lin-15 locus controls two separate genetic activities. Mutants that lack both activities have multiple, ectopic pseudo-vulvae resulting from the overproduction of vulval cells, whereas mutants defective in only one lin-15 activity appear wild-type. lin-15 acts non-cell-autonomously to prevent the activation of a receptor tyrosine kinase/ras signaling pathway. We report here the molecular characterization of the lin-15 locus. The two lin-15 activities are encoded by contiguous genomic regions and by two distinct, non-overlapping transcripts that may be processed from a single mRNA precursor by trans-splicing. Based on the DNA sequence, the 719- and 1,440-amino acid lin-15 proteins are not similar to each other or to known proteins. lin-15 multivulva mutants, which are defective in both lin-15 activities, contain deletions and insertions that affect the lin-15 genomic region.},
author = {Clark, S. G. and Lu, X. and Horvitz, H. R.},
doi = {10.1038/348503a0},
isbn = {0016-6731 (Print)$\backslash$r0016-6731 (Linking)},
issn = {00166731},
journal = {Genetics},
month = {dec},
number = {4},
pages = {987--997},
pmid = {7982579},
publisher = {Nature Publishing Group},
title = {{The  \emph{Caenorhabditis~elegans} locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins}},
volume = {137},
year = {1994}
}
@article{Stewart1999,
abstract = {Genetic screens for modifiers of activated Ras phenotypes have identified a novel protein, kinase suppressor of Ras (KSR), which shares significant sequence homology with Raf family protein kinases. Studies using Drosophila melanogaster and  \emph{Caenorhabditis~elegans} predict that KSR positively regulates Ras signaling; however, the function of mammalian KSR is not well understood. We show here that two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1 loss-of-function alleles in \emph{C.~elegans} , suggesting that KSR may have physiological, kinase-independent functions. Furthermore, we observe that murine KSR forms a multimolecular signaling complex in human embryonic kidney 293T cells composed of HSP90, HSP70, HSP68, p50(CDC37), MEK1, MEK2, 14-3-3, and several other, unidentified proteins. Treatment of cells with geldanamycin, an inhibitor of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to stabilize KSR. Both nematode and mammalian KSRs are capable of binding to MEKs, and three-point mutants of KSR, corresponding to \emph{C.~elegans}  loss-of-function alleles, are specifically compromised in MEK binding. KSR did not alter MEK activity or activation. However, KSR-MEK binding shifts the apparent molecular mass of MEK from 44 to {\textgreater}700 kDa, and this results in the appearance of MEK in membrane-associated fractions. Together, these results suggest that KSR may act as a scaffolding protein for the Ras-mitogen-activated protein kinase pathway.},
author = {Stewart, S and Sundaram, M and Zhang, Y and Lee, J and Han, M and Guan, K L},
doi = {10.1128/MCB.19.8.5523},
file = {:Users/dangeles/Documents/Mendeley Desktop/Stewart et al. - 1999 - Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization.pdf:pdf},
issn = {0270-7306},
journal = {Molecular and cellular biology},
month = {aug},
number = {8},
pages = {5523--34},
pmid = {10409742},
publisher = {American Society for Microbiology},
title = {{Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization.}},
volume = {19},
year = {1999}
}
@article{Gu1998,
abstract = {The let-60 ras gene acts in a signal transduction pathway to control vulval differentiation in  \emph{Caenorhabditis~elegans}  . By screening suppressors of a dominant negative let-60 ras allele, we isolated three loss-of-function mutations in the sur-5 gene which appear to act as negative regulators of let-60 ras during vulval induction. sur-5 mutations do not cause an obvious mutant phenotype of their own, and they appear to specifically suppress only one of the two groups of let-60 ras dominant negative mutations, suggesting that the gene may be involved in a specific aspect of Ras activation. Consistent with its negative function, overexpressing sur-5 from an extragenic array partially suppresses the Multivulva phenotype of an activated let-60 ras mutation and causes synergistic phenotypes with a lin-45 raf mutation. We have cloned sur-5 and shown that it encodes a novel protein. We have also identified a potential mammalian SUR-5 homolog that is about 35{\%} identical to the worm protein. SUR-5 also has some sequence similarity to acetyl coenzyme A synthetases and is predicted to contain ATP/GTP and AMP binding sites. Our results suggest that sur-5 gene function may be conserved through evolution.},
author = {Gu, T and Orita, S and Han, M},
doi = {10.1128/MCB.18.8.4556},
file = {:Users/dangeles/Documents/Mendeley Desktop/Gu, Orita, Han - 1998 -  \emph{Caenorhabditis~elegans} SUR-5, a novel but conserved protein, negatively regulates LET-60 Ras activity during vul.pdf:pdf},
issn = {0270-7306},
journal = {Molecular and cellular biology},
month = {aug},
number = {8},
pages = {4556--64},
pmid = {9671465},
publisher = {American Society for Microbiology},
title = {{Caenorhabditis elegans SUR-5, a novel but conserved protein, negatively regulates LET-60 Ras activity during vulval induction.}},
volume = {18},
year = {1998}
}
@article{Wu1995,
abstract = {Activated Ras initiates a cascade of sequential phosphorylation events, including the protein kinases Raf, MEK, and MAP kinase. The Let-60 Ras-mediated signal transduction pathway controls vulval induction in  \emph{Caenorhabditis~elegans}  . Both Lin-45 Raf and Sur-1 MAP kinase have been determined to be essential factors during vulval induction; however, the \emph{C.~elegans}  mek gene has not been identified. In this paper, we have cloned a \emph{C.~elegans}  mek gene, mek-2, and demonstrated that the MEK-2 protein possesses the biochemical properties of MAP kinase kinases: The \emph{C.~elegans}  MEK-2 protein can phosphorylate and activate a human MAP kinase (ERK1), and MEK-2 itself can be phosphorylated and activated by immunoprecipitated mammalian Raf. The mek-2 gene plays a key role in the let-60 ras-mediated vulval induction pathway, as loss-of-function mutations in the gene (ku114 and h294) significantly reduce the signal transmitted through Ras. mek-2(ku114) completely suppressed the Multivulva (Muv) phenotype of a hyperactive let-60 ras mutation, and animals homozygous for mek-2(ku114) also displayed a partial larval lethal phenotype. Animals homozygous for mek-2(h294) exhibited a highly penetrant sterile and Vulvaless phenotype. Microinjection of a gain-of-function mek-2 mutation resulted in Muv and other mutant phenotypes, whereas microinjection of a dominant-negative mutation not only suppressed the Muv phenotype of an activated let-60 ras mutation but also caused an egg-laying defective phenotype in otherwise wild type animals. Our results demonstrate that mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events.},
author = {Wu, Yan and Han, Min and Guan, Kun Liang},
doi = {10.1101/gad.9.6.742},
isbn = {0890-9369 (Print)},
issn = {08909369},
journal = {Genes and Development},
keywords = {C. elegans,MAP kinase kinase,Signal transduction,Vulval induction,mek-2,ras},
number = {6},
pages = {742--755},
pmid = {7729690},
title = {{MEK-2, a  \emph{Caenorhabditis~elegans} MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events}},
volume = {9},
year = {1995}
}
@article{Clark1992,
author = {Clark, Scott G. and Stern, Michael J. and Horvritz, H. Robert},
doi = {10.1038/356340a0},
issn = {0028-0836},
journal = {Nature},
month = {mar},
number = {6367},
pages = {340--344},
publisher = {Nature Publishing Group},
title = {{\emph{C.~elegans} cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains}},
volume = {356},
year = {1992}
}

@article{Han1993a,
author = {Han, Min and Golden, Andy and Han, Yuming and Sternberg, Paul W.},
doi = {10.1038/363133a0},
issn = {0028-0836},
journal = {Nature},
month = {may},
number = {6425},
pages = {133--140},
publisher = {Nature Publishing Group},
title = {{\emph{C.~elegans} lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation}},
volume = {363},
year = {1993}
}
@article{Muratcioglu2015,
abstract = {Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated $\beta$-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer.},
author = {Muratcioglu, Serena and Chavan, Tanmay?S. and Freed, Benjamin?C. and Jang, Hyunbum and Khavrutskii, Lyuba and Freed, R.?Natasha and Dyba, Marzena?A. and Stefanisko, Karen and Tarasov, Sergey?G. and Gursoy, Attila and Keskin, Ozlem and Tarasova, Nadya?I. and Gaponenko, Vadim and Nussinov, Ruth},
doi = {10.1016/j.str.2015.04.019},
file = {:Users/dangeles/Documents/Mendeley Desktop/Muratcioglu et al. - 2015 - GTP-Dependent K-Ras Dimerization.pdf:pdf},
issn = {09692126},
journal = {Structure},
month = {jul},
number = {7},
pages = {1325--1335},
pmid = {26051715},
publisher = {Elsevier},
title = {{GTP-Dependent K-Ras Dimerization}},
volume = {23},
year = {2015}
}
@article{Sieburth1998,
author = {Sieburth, Derek S and Sun, Qun and Han, Min},
doi = {10.1016/S0092-8674(00)81227-1},
issn = {00928674},
journal = {Cell},
month = {jul},
number = {1},
pages = {119--130},
title = {{SUR-8, a Conserved Ras-Binding Protein with Leucine-Rich Repeats, Positively Regulates Ras-Mediated Signaling in \emph{C.~elegans} }},
volume = {94},
year = {1998}
}
@article{Han1990,
abstract = {During induction of the  \emph{Caenorhabditis~elegans} hermaphrodite vulva by the anchor cell of the gonad, six multipotent vulval precursor cells (VPCs) have two distinct fates: three VPCs generate the vulva and the other three VPCs generate nonspecialized hypodermis. Genes that control the fates of the VPCs in response to the anchor cell signal are defined by mutations that cause all six VPCs to generate vulval tissue (Multivulva or Muv) or that cause all six VPCs to generate hypodermis (Vulvaless or Vul). Seven dominant Vul mutations were isolated as dominant suppressors of a lin-15 Muv mutation. These mutations are dominant alleles of the gene let-60, previously identified only by recessive lethal mutations. Our genetic studies of these dominant Vul recessive lethal mutations, recessive lethal mutations, intragenic revertants of the dominant Vul mutations, and the closely mapping semi-dominant multivulva lin-34 mutations suggest that: (1) loss-of-function mutations of let-60 are recessive lethal at a larval stage, but they also cause a Vul phenotype if the lethality is rescued maternally by a lin-34 gain-of-function mutation. (2) The dominant Vul alleles of let-60 are dominant negative mutations whose gene products compete with wild-type activity. (3) lin-34 semidominant Muv alleles are either gain-of-function mutations of let-60 or gain-of-function mutations of an intimately related gene that elevates let-60 activity. We propose that let-60 activity controls VPC fates. In a wild-type animal, reception by a VPC of inductive signal activates let-60, and it generates into a vulval cell type; in absence of inductive signal, let-60 activity is low and the VPC generates hypodermal cells. Our genetic interaction studies suggest that let-60 acts downstream of let-23 and lin-15 and upstream of lin-1 and lin-12 in the genetic pathway specifying the switch between vulval and nonvulval cell types.},
author = {Han, M. and Aorian, R. V. and Sternberg, P. W.},
doi = {10.1038/348693a0},
issn = {00166731},
journal = {Genetics},
number = {4},
pages = {899--913},
pmid = {2076820},
title = {{The let-60 locus controls the switch between vulval and nonvulval cell fates in  \emph{Caenorhabditis~elegans}}},
volume = {126},
year = {1990}
}
@article{Wu1995a,
abstract = {Activated Ras initiates a cascade of sequential phosphorylation events, including the protein kinases Raf, MEK, and MAP kinase. The Let-60 Ras-mediated signal transduction pathway controls vulval induction in  \emph{Caenorhabditis~elegans}  . Both Lin-45 Raf and Sur-1 MAP kinase have been determined to be essential factors during vulval induction; however, the \emph{C.~elegans}  mek gene has not been identified. In this paper, we have cloned a \emph{C.~elegans}  mek gene, mek-2, and demonstrated that the MEK-2 protein possesses the biochemical properties of MAP kinase kinases: The \emph{C.~elegans}  MEK-2 protein can phosphorylate and activate a human MAP kinase (ERK1), and MEK-2 itself can be phosphorylated and activated by immunoprecipitated mammalian Raf. The mek-2 gene plays a key role in the let-60 ras-mediated vulval induction pathway, as loss-of-function mutations in the gene (ku114 and h294) significantly reduce the signal transmitted through Ras. mek-2(ku114) completely suppressed the Multivulva (Muv) phenotype of a hyperactive let-60 ras mutation, and animals homozygous for mek-2(ku114) also displayed a partial larval lethal phenotype. Animals homozygous for mek-2(h294) exhibited a highly penetrant sterile and Vulvaless phenotype. Microinjection of a gain-of-function mek-2 mutation resulted in Muv and other mutant phenotypes, whereas microinjection of a dominant-negative mutation not only suppressed the Muv phenotype of an activated let-60 ras mutation but also caused an egg-laying defective phenotype in otherwise wild type animals. Our results demonstrate that mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events.},
author = {Wu, Yan and Han, Min and Guan, Kun Liang},
doi = {10.1101/gad.9.6.742},
isbn = {0890-9369 (Print)},
issn = {08909369},
journal = {Genes and Development},
keywords = {C. elegans,MAP kinase kinase,Signal transduction,Vulval induction,mek-2,ras},
number = {6},
pages = {742--755},
pmid = {7729690},
title = {{MEK-2, a  \emph{Caenorhabditis~elegans} MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events}},
volume = {9},
year = {1995}
}
@article{Sundaram1996,
author = {Sundaram, M. and Yochem, J. and Han, M.},
journal = {Development},
number = {9},
title = {{A Ras-mediated signal transduction pathway is involved in the control of sex myoblast migration in  \emph{Caenorhabditis~elegans}  }},
volume = {122},
year = {1996}
}

@article{Euling1996,
author = {Euling, S. and Ambros, V.},
journal = {Development},
number = {8},
title = {{Reversal of cell fate determination in  \emph{Caenorhabditis~elegans} vulval development}},
volume = {122},
year = {1996}
}

@article{Zand2011,
abstract = {The \emph{C.~elegans}  vulva is patterned by epidermal growth factor (EGF) activation of Ras to control 1° fate, and 1° fate induces antagonistic Notch-dependent 2° fate. Furthermore, a spatial EGF gradient, in addition to inducing 1° fate, directly contributes to 2° fate via an unknown pathway. We find that in addition to its canonical effector, Raf, vulval Ras utilizes an exchange factor for the Ral small GTPase (RalGEF), such that Ras-RalGEF-Ral antagonizes Ras-Raf pro-1° fate activity. Consistent with its restricted expression pattern, Ral participates in EGF pro-2° activity. Thus, we have delineated a Ras effector-switching mechanism whereby position within the morphogen gradient dictates that Ras effector usage is switched to RalGEF from Raf to promote 2° instead of 1° fate. Our observations define the utility of Ras effector switching during normal development and may provide a possible mechanistic basis for cell and cancer-type differences in effector dependency and activation.},
author = {Zand, Tanya P. and Reiner, David J. and Der, Channing J.},
doi = {10.1016/j.devcel.2010.12.004},
issn = {15345807},
journal = {Developmental Cell},
number = {1},
pages = {84--96},
title = {{Ras Effector Switching Promotes Divergent Cell Fates in \emph{C.~elegans}  Vulval Patterning}},
volume = {20},
year = {2011}
}

@article{Ferguson1985,
author = {Ferguson, Edwin L. and Horvitz, H. Robert},
journal = {Genetics},
number = {1},
title = {{IDENTIFICATION AND CHARACTERIZATION OF 22 GENES THAT AFFECT THE VULVAL CELL LINEAGES OF THE NEMATODE  \emph{Caenorhabditis~elegans}  }},
volume = {110},
year = {1985}
}

@article{Solari2000,
author = {Solari, Florence and Ahringer, Julie},
doi = {10.1016/S0960-9822(00)00343-2},
issn = {09609822},
journal = {Current Biology},
month = {Feb},
number = {4},
pages = {223--226},
title = {{NURD-complex genes antagonise Ras-induced vulval development in  \emph{Caenorhabditis~elegans}  }},
volume = {10},
year = {2000}
}

@article{Tiensuu2005a,
abstract = {lin-1 encodes an ETS domain transcription factor that functions downstream of a Ras/MAP kinase pathway mediating induction of the 1° cell fate during vulval development in the \emph{C.~elegans}  hermaphrodite. Mutants lacking lin-1 activity display a phenotype similar to that caused by mutations that constitutively activate let-60 Ras consistent with a model in which lin-1 is a repressor of the 1° fate whose activity is inhibited by phosphorylation by MPK-1 MAP kinase. Here, we show that, contrary the current model, lin-1 is required positively for the proper expression of several genes regulated by the pathway in cells adopting the 1° cell fate. We show that the positive requirement for lin-1 is downstream of let-60 Ras and mpk-1 MAP kinase, and that it has a focus in the vulval precursor cells themselves. lin-1 alleles encoding proteins lacking a docking site for MPK-1 MAP kinase are defective in the positive function. We also show that lin-1 apparently has both positive and negative functions during the specification of the fates of other cells in the worm requiring Ras/MAP kinase signaling.},
author = {Tiensuu, Teresa and Larsen, Morten Krog and Vernersson, Emma and Tuck, Simon},
doi = {10.1016/j.ydbio.2005.08.007},
issn = {00121606},
journal = {Developmental Biology},
number = {1},
pages = {338--351},
title = {{lin-1 has both positive and negative functions in specifying multiple cell fates induced by Ras/MAP kinase signaling in \emph{C.~elegans} }},
volume = {286},
year = {2005}
}

@article{Moghal2003,
abstract = {Negative regulation of receptor tyrosine kinase (RTK)/RAS signaling pathways is important for normal development and the prevention of disease in humans. We have used a genetic screen in \emph{C.~elegans}  to identify genes that antagonize the activity of activated LET-23, a member of the EGFR family of RTKs. We identified two loss-of-function mutations in dpy-22, previously cloned as sop-1, that promote the ability of activated LET-23 to induce ectopic vulval fates. DPY-22 is a glutamine-rich protein that is most similar to human TRAP230, a component of a transcriptional mediator complex. DPY-22 has previously been shown to regulate WNT responses through inhibition of the beta-catenin-like protein BAR-1. We provide evidence that DPY-22 also inhibits RAS-dependent vulval fate specification independently of BAR-1, and probably regulates the activities of multiple transcription factors during development. Furthermore, we demonstrate that although inhibition of BAR-1-dependent gene expression has been shown to require the C-terminal glutamine-rich region, this region is dispensable for inhibition of RAS-dependent cell differentiation. Thus, the glutamine-rich region contributes to specificity of this class of mediator protein.},
author = {Moghal, N.},
doi = {10.1242/dev.00189},
isbn = {0950-1991 (Print)
0950-1991 (Linking)},
issn = {09501991},
journal = {Development},
number = {1},
pages = {57--69},
pmid = {12441291},
title = {{A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in \emph{C.~elegans} }},
volume = {130},
year = {2003}
}

@article{Howard2002,
abstract = {In  \emph{Caenorhabditis~elegans}  , Ras/ERK and Wnt/beta-catenin signaling pathways cooperate to induce P12 and vulval cell fates in a Hox-dependent manner. Here we describe eor-1 and eor-2, two new positively acting nuclear components of the Ras and Wnt pathways. eor-1 and eor-2 act downstream or in parallel to ERK and function redundantly with the Mediator complex gene sur-2 and the functionally related gene lin-25, such that removal of both eor-1/eor-2 and sur-2/lin-25 mimics the removal of a main Ras pathway component. Furthermore, the eor-1 and eor-2 mutant backgrounds reveal an essential role for the Elk1-related gene lin-1. eor-1 and eor-2 also act downstream or in parallel to pry-1 Axin and therefore act at the convergence of the Ras and Wnt pathways. eor-1 encodes the ortholog of human PLZF, a BTB/zinc-finger transcription factor that is fused to RARalpha in acute promyelocytic leukemia. eor-2 encodes a novel protein. EOR-1/PLZF and EOR-2 appear to function closely together and cooperate with Hox genes to promote the expression of Ras- and Wnt-responsive genes. Further studies of eor-1 and eor-2 may provide insight into the roles of PLZF in normal development and leukemogenesis.},
author = {Howard, Robyn M and Sundaram, Meera V},
doi = {10.1101/gad.998402},
file = {:Users/dangeles/Documents/Mendeley Desktop/Howard, Sundaram - 2002 - \emph{C.~elegans}  EOR-1PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25.pdf:pdf},
issn = {0890-9369},
journal = {Genes {\&} development},
month = {jul},
number = {14},
pages = {1815--27},
pmid = {12130541},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{\emph{C.~elegans} EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component.}},
volume = {16},
year = {2002}
}

@article{Angeles-Albores2016,
author = {Angeles-Albores, David and {N. Lee}, Raymond Y. and Chan, Juancarlos and Sternberg, Paul W.},
doi = {10.1186/s12859-016-1229-9},
file = {:Users/dangeles/Documents/Mendeley Desktop/Angeles-Albores et al. - 2016 - Tissue enrichment analysis for \emph{C.~elegans}  genomics.pdf:pdf},
issn = {1471-2105},
journal = {BMC Bioinformatics},
keywords = {anatomy ontology,gene ontology,high-throughput biology,rna-seq,wormbase},
number = {1},
pages = {366},
publisher = {BMC Bioinformatics},
title = {{Tissue enrichment analysis for \emph{C.~elegans}  genomics}},
volume = {17},
year = {2016}
}

@article{Vaid2013,
author = {Vaid, Samir and Ariz, Mohd and Chaturbedi, Amaresh and Kumar, Ganga Anil and Subramaniam, Kuppuswamy},
journal = {Development},
number = {8},
title = {{PUF-8 negatively regulates RAS/MAPK signalling to promote differentiation of \emph{C.~elegans}  germ cells}},
volume = {140},
year = {2013}
}

@article{Euling1996a,
author = {Euling, S. and Ambros, V.},
journal = {Development},
number = {8},
title = {{Reversal of cell fate determination in  \emph{Caenorhabditis~elegans} vulval development}},
volume = {122},
year = {1996}
}

@article{Sternberg1995,
abstract = {We are using  \emph{Caenorhabditis~elegans} vulval induction to study intercellular signaling and its regulation. Genes required for vulval induction include the LIN-3 transforming alpha-like growth factor, the LET-23 epidermal growth factor (EGF)-receptor-like transmembrane tyrosine kinase, the SEM-5 adaptor protein, LET-60 Ras, and the LIN-45 Raf serine/threonine kinase. Inactivation of this pathway results in a failure of vulval differentiation, the "vulvaless" phenotype. Activation of this pathway either by overexpression of LIN-3, a point mutation in the LET-23 extracellular domain, or hyperactivity of LET-60 Ras results in excessive vulval differentiation, the "multivulva" phenotype. In addition to searching for new genes that act positively in this signaling pathway, we have also characterized genes that negatively regulate this inductive signaling pathway. We find that such negative regulators are functionally redundant: mutation of only one of these negative regulators has no effect on vulval differentiation; however, if particular combinations of these genes are inactivated, excessive vulval differentiation occurs. The LIN-15 locus encodes two functionally redundant products, LIN-15A and LIN-15B, that formally act upstream of the LET-23 receptor to prevent its activity in the absence of inductive signal. The LIN-15A and B proteins are novel and unrelated to each other. The unc-101, sli-1, and rok-1 genes encode a distinct set of negative regulators of vulval differentiation. The unc-101 gene encodes an adaptin, proposed to be involved in intracellular protein trafficking. The sli-1 gene encodes a protein with similarity to c-cbl, a mammalian proto-oncogene not previously linked with a tyrosine kinase-Ras-mediated signaling pathway. LIN-3 and LET-23 are required for several aspects of \emph{C.~elegans}  development--larval viability, P12 neuroectoblast specification, hermaphrodite vulval induction and fertility, and three inductions during male copulatory spicule development. Fertility and vulval differentiation appear to be mediated by distinct parts of the cytoplasmic tail of LET-23, and by distinct signal transduction pathways.},
author = {Sternberg, Paul W. and Lesa, Giovanni and Lee, Junho and Katz, Wendy S. and Yoon, Charles and Clandinin, Thomas R. and Huang, Linda S. and Chamberlin, Helen M. and Jongeward, Gregg},
doi = {10.1002/mrd.1080420422},
file = {:Users/dangeles/Documents/Mendeley Desktop/Sternberg et al. - 1995 - LET-23-mediated signal transduction duringCaenorhabditis elegans development.pdf:pdf},
issn = {10982795},
journal = {Molecular Reproduction and Development},
keywords = {Growth factor,Induction,Nematode,Receptor tyrosine kinase,Tissue specificity},
month = {dec},
number = {4},
pages = {523--528},
pmid = {8607985},
publisher = {Wiley Subscription Services, Inc., A Wiley Company},
title = {{LET-23-mediated signal transduction during  \emph{Caenorhabditis~elegans} development}},
volume = {42},
year = {1995}
}

@article{Nan2015,
abstract = {Rat sarcoma (Ras) GTPases regulate cell proliferation and survival through effector pathways including Raf-MAPK, and are the most frequently mutated genes in human cancer. Although it is well established that Ras activity requires binding to both GTP and the membrane, details of how Ras operates on the cell membrane to activate its effectors remain elusive. Efforts to target mutant Ras in human cancers to therapeutic benefit have also been largely unsuccessful. Here we show that Ras-GTP forms dimers to activate MAPK. We used quantitative photoactivated localization microscopy (PALM) to analyze the nanoscale spatial organization of PAmCherry1-tagged KR

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