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Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements.
Angeles-Albores, David; Puckett Robinson, Carmie; Williams, Brian A; Wold, Barbara J; Sternberg, Paul W.
Affiliation
  • Angeles-Albores D; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
  • Puckett Robinson C; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125.
  • Williams BA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
  • Wold BJ; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125.
  • Sternberg PW; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Proc Natl Acad Sci U S A ; 115(13): E2930-E2939, 2018 03 27.
Article in En | MEDLINE | ID: mdl-29531064
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.
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Full text: 1 Database: MEDLINE Main subject: Caenorhabditis elegans / Caenorhabditis elegans Proteins / Epistasis, Genetic / Gene Regulatory Networks / High-Throughput Nucleotide Sequencing / Transcriptome Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2018 Type: Article

Full text: 1 Database: MEDLINE Main subject: Caenorhabditis elegans / Caenorhabditis elegans Proteins / Epistasis, Genetic / Gene Regulatory Networks / High-Throughput Nucleotide Sequencing / Transcriptome Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2018 Type: Article