The Mediator complex of Caenorhabditis elegans: insights into the developmental and physiological roles of a conserved transcriptional coregulator

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 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/β-catenin signaling. More recently, important roles for 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 C. elegans ortholog mdt-12 as a regulatory hub that interacts with numerous signaling pathways.

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

“…Previous studies (reviewed in Grants et al 2015) and our data show that several core Mediator subunits promote C. elegans vulva development, whereas CKM subunits inhibit this process. This suggested that intra-Mediator regulation might coordinate gene expression downstream of the EGFR-Ras-ERK signaling pathway that drives vulva development.…”

“…Several Mediator subunits positively or negatively regulate EGFR signaling-driven developmental processes (reviewed in Grants et al 2015), but pertinent mechanisms remain incompletely understood. Here, we used the well-characterized vulva development paradigm in C. elegans to delineate the role of the Mediator CKM module.…”

“…As several Mediator subunits positively regulate vulva development (reviewed in Grants et al 2015), we hypothesized that the CKM might function in part by inhibiting these subunits. In wild-type worms, the mdt-23/sur-2 tail module subunit is critical for vulva development downstream of Ras (Singh and Han 1995), and it is required for activation of the EGFR signaling target gene lag-2 (Zhang and Greenwald 2011); therefore, we tested how a mutation in a CKM subunit affected vulval induction in mdt-23/sur-2 mutants.…”

“…In addition, multiple chromatin-modifying complexes, encoded by the synthetic multivulva (synMuv) genes, redundantly repress ectopic lin-3/EGF transcription in the hypodermis and other tissues to inhibit 1°cell fate specification in VPCs other than P6.p (Myers and Greenwald 2005;Cui et al 2006;Saffer et al 2011). Furthermore, the Mediator subunits mdt-23/sur-2, mdt-24/lin-25, and mdt-6 promote vulva development, whereas the CKM subunit mdt-12/dpy-22 inhibits vulva development in an anchor cell-independent manner (reviewed in Grants et al 2015); for standardized Mediator subunit nomenclature, please see Bourbon et al (2004). The mechanism by which mdt-23/sur-2 promotes vulva development has been partially elucidated, as it is a critical coactivator of a target gene downstream of the EGFR signaling pathway, the lag-2 Notch ligand gene (Zhang and Greenwald 2011).…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…Indeed, MED12 encodes a subunit of a "kinase module," which includes cyclin C and cyclindependent kinase (CDK) 8/CDK19, that belongs to a large protein complex implicated in many activities, including the regulation of transcription, chromatin architecture and enhancer-promoter gene looping in interaction with cohesin and noncoding RNA [111][112][113]. In Caenorhabditis elegans, the MED12 ortholog may work as an integration hub for several signaling pathways, including EGFR, Notch and Wnt signaling [113,114] and it has been reported to modulate the response to EGFR, ALK and BRAF inhibitors by negatively regulating transforming growth factor b (TGF-b) receptor 2 in mammalian cells [115].…”