Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements.
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Caenorhabditis elegans
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Caenorhabditis elegans Proteins
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Epistasis, Genetic
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Gene Regulatory Networks
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High-Throughput Nucleotide Sequencing
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Transcriptome
Limits:
Animals
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2018
Type:
Article