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Using Transcriptomes as Mutant Phenotypes Reveals Functional Regions of a Mediator Subunit in Caenorhabditis elegans.

ABSTRACT: Although transcriptomes have recently been used as phenotypes with which to perform epistasis analyses, they are not yet used to study intragenic function/structure relationships. We developed a theoretical framework to study allelic series using transcriptomic phenotypes. As a proof-of-concept, we apply our methods to an allelic series of dpy-22, a highly pleiotropic Caenorhabditis elegans gene orthologous to the human gene MED12, which encodes a subunit of the Mediator complex. Our methods identify functional units within dpy-22 that modulate Mediator activity upon various genetic programs, including the Wnt and Ras modules.

SUBMITTER: Angeles-Albores D

PROVIDER: S-EPMC6116950 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Using Transcriptomes as Mutant Phenotypes Reveals Functional Regions of a Mediator Subunit in Caenorhabditis elegans.

Angeles-Albores David D Sternberg Paul W PW

Genetics 20180720 1

Although transcriptomes have recently been used as phenotypes with which to perform epistasis analyses, they are not yet used to study intragenic function/structure relationships. We developed a theoretical framework to study allelic series using transcriptomic phenotypes. As a proof-of-concept, we apply our methods to an allelic series of dpy-22, a highly pleiotropic Caenorhabditis elegans gene orthologous to the human gene MED12, which encodes a subunit of the Mediator com ...[more]

PMID: 30030292

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Project description:Zinc is essential for cellular functions as it is a catalytic and structural component of many proteins. In contrast, cadmium is not required in biological systems and is toxic. Zinc and cadmium levels are closely monitored and regulated as their excess causes cell stress. To maintain homeostasis, organisms induce metal detoxification gene programs through stress responsive transcriptional regulatory complexes. In Caenorhabditis elegans, the MDT-15 subunit of the evolutionarily conserved Mediator transcriptional coregulator is required to induce genes upon exposure to excess zinc and cadmium. However, the regulatory partners of MDT-15 in this response, its role in cellular and physiological stress adaptation, and the putative role for mammalian MED15 in the metal stress responses remain unknown. Here, we show that MDT-15 interacts physically and functionally with the Nuclear Hormone Receptor HIZR-1 to promote molecular, cellular, and organismal adaptation to cadmium and excess zinc. Using gain- and loss-of-function mutants and qRT-PCR and reporter analysis, we find that mdt-15 and hizr-1 cooperate to induce zinc and cadmium responsive genes. Moreover, the two proteins interact physically in yeast-two-hybrid assays and this interaction is enhanced by the addition of zinc or cadmium, the former a known ligand of HIZR-1. Functionally, mdt-15 and hizr-1 mutants show defective storage of excess zinc in the gut and are hypersensitive to zinc-induced reductions in egg-laying. Furthermore, mdt-15 but not hizr-1 mutants are hypersensitive to cadmium-induced reductions in egg-laying, suggesting potential divergence of regulatory pathways. Lastly, mammalian MDT-15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium and zinc-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 cooperate to regulate cadmium detoxification and zinc storage and that this mechanism is at least partially conserved in mammals.

Dataset Information

Using Transcriptomes as Mutant Phenotypes Reveals Functional Regions of a Mediator Subunit in Caenorhabditis elegans.

Publications

Using Transcriptomes as Mutant Phenotypes Reveals Functional Regions of a Mediator Subunit in <i>Caenorhabditis elegans</i>.

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