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Study of an allelic series using transcriptomic phenotypes

ABSTRACT: Expression profiling holds great promise for genetics because of its ability to measure thousands of genes quantitatively. Although transcriptomes have recently been used to perform epistasis analyses for pathway reconstruction, there has not been a systematic effort to understand how expression profiles will vary among distinct mutants of the same gene. Here, we study an allelic series in C. elegans consisting of one wild type and two mutant alleles of mdt-12, a highly pleiotropic gene whose gene product is a subunit of Mediator complex, which is essential for transcriptional regulation in eukaryotes. We developed a false hit analysis to identify which populations of genes commonly differentially expressed with respect to the wild type are likely the result of statistical artifact. We concluded that expression perturbations caused by these alleles split into four distinct modules called phenotypic classes. To understand the dominance relationship between the two mutant alleles, we developed a dominance analysis for transcriptional data. Dominance analysis of these phenotypic classes support a model where mdt-12 has multiple functional units that function independently to target the Mediator complex to specific genetic loci.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE107523 | GEO | 2020/01/01

REPOSITORIES: GEO

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Proteomic interactome of C. elegans Mediator complex subunit 28 (MDT-28) reveals predominant association with a restricted set of core Mediator subunits and an affinity to additional structural and enzymatic proteins

Project description:Transcription factors exert their regulatory potential on RNA Polymerase II machinery through a multiprotein complex called Mediator complex or Mediator. The Mediator complex integrates regulatory signals from cell regulatory cascades with the regulation by transcription factors. The Mediator complex consists of 25 subunits in Saccharomyces cerevisiae and 30 or more subunits in multicellular eukaryotes. Mediator subunit 28 (MED28), along with MED30, MED23, MED25 and MED26 belong to presumably evolutionarily new subunits that seem to be absent in unicellular eukaryotes and are likely to have evolved together with multicellularity and cell differentiation. Previously, we have shown that an originally uncharacterized predicted gene F28F8.5 is the true MED28 orthologue in Caenorhabditis elegans (MDT-28) and showed that it is involved in a spectrum of developmental processes. Here, we studied the proteomic interactome of MDT-28 edited as GFP::MDT-28 using Crispr/Cas9 technology or MDT-28::GFP expressed from extrachromosomal arrays in transgenic C. elegans exploiting the GFP-TRAP system and mass spectrometry. The results show that MDT-28 associates with the Head module subunits MDT-6, MDT-8, MDT-11, MDT-17, MDT-20, MDT-22 and MDT-30 and the Middle module subunit MDT-14. The analyses also identified additional proteins as preferential MDT-28 interactants including chromatin organizing proteins, structural proteins and enzymes. The results provide evidence for MDT-28 engagement in the Mediator Head Module and support the possibility of physical (direct or indirect) interaction of MDT-28 with additional proteins, reflecting a transcription-regulating potential of primarily structural and enzymatic proteins at the level of the Mediator complex.

2020-07-15 | PXD015552 | Pride

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Microarray expression profiling of C. elegans N2 L4 control(RNAi) vs. mdt-15(RNAi)

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Genomewide expression profiling of multibacillary leprosy lesions before and after multi-drug therapy (MDT)

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Project description:Ultimately, the genotype of a cell and its interaction with the environment determine the cell’s biochemical state. While the cell’s response to a single stimulus has been studied extensively, a conceptual framework to model the effect of multiple environmental stimuli applied concurrently is not as well developed. In this study, we developed the concepts of environmental interactions and epistasis to explain the responses of the S. cerevisiae proteome to simultaneous environmental stimuli. We hypothesize that, as an abstraction, environmental stimuli can be treated as analogous to genetic elements. This would allow modeling of the effects of multiple stimuli using the concepts and tools developed for studying gene interactions. Mirroring gene interactions, our results show that environmental interactions play a critical role in determining the state of the proteome. We show that individual and complex environmental stimuli behave similarly to genetic elements in regulating the cellular responses to stimuli, including the phenomena of dominance and suppression. Interestingly, we observed that the effect of a stimulus on a protein is dominant over other stimuli if the response to the stimulus involves the protein. Using publicly available transcriptomic data, we find that environmental interactions and epistasis regulate transcriptomic responses as well.

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Dominance hierarchy arising from the evolution of a complex small RNA regulatory network

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Gene and allele specific expression during electric organ ontogeny in African weakly electric fish and hybrid

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