The Mediator complex: a master coordinator of transcription and cell lineage development

Abstract

Mediator is a multiprotein complex that is required for gene transcription by RNA polymerase II. Multiple subunits of the complex show specificity in relaying information from signals and transcription factors to the RNA polymerase II machinery, thus enabling control of the expression of specific genes. Recent studies have also provided novel mechanistic insights into the roles of Mediator in epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation and super enhancer formation. Based on these specific roles in gene regulation, Mediator has emerged as a master coordinator of development and cell lineage determination. Here, we describe the most recent advances in understanding the mechanisms of Mediator function, with an emphasis on its role during development and disease. KEY WORDS: Mediator complex, Transcription, Cell fate, Lineage development, Disease IntroductionMediator is a large, multisubunit complex that was discovered following efforts to understand how RNA polymerase II (Pol II)-mediated transcription is regulated by transcription factors in yeast (Nonet and Young, 1989;Kelleher et al., 1990;Thompson et al., 1993;Kim et al., 1994). The complex, which consists of ~30 polypeptides ( Fig. 1), shows conservation from yeast to humans and plays an indispensable role in regulating transcription. Multiple laboratories then used a variety of procedures to isolate mammalian Mediator complexes, which were named TRAP/SMCC, NAT, ARC, DRIP, Srb/MED, PC2, CRSP and mouse Mediator (Jiang et al., 1998;Sun et al., 1998; Boyer et al., 1999;Ito et al., 1999;Kingston, 1999;Näär et al., 1999;Rachez et al., 1999;Ryu et al., 1999;Malik et al., 2000). In 2004, a unified nomenclature for Mediator was established, consisting of MED1 to MED31, together with the cyclin-dependent kinase (CDK) 8-cyclin C pair and several paralogs such as MED1-like (MED1L), MED12L, MED13L and CDK19 (Bourbon et al., 2004). The Mediator complex can be divided into four distinct modules termed the head, middle, tail and CDK8 kinase module, which contains CDK8 (or its paralog CDK19), cyclin C, MED12 (or MED12L) and MED13 (or MED13L) subunits (Malik and Roeder, 2010;Taatjes, 2010). Importantly, the subunit composition of Mediator can vary and is not restricted to a single isoform. For example, immunodepletion of the Mediator complex from HeLa nuclear extracts with an anti-CDK8 antibody revealed that Mediator exists as at least two main isoforms, distinguished by the presence or absence of the CDK8 submodule (Wang et al., 2001). In addition, MED1 and MED26 are not present in all isolated isoforms (Malik and Roeder, 2010).After the initial discovery of Mediator, research mainly focused on how the Mediator complex conveys signals from transcription factors to the Pol II machinery and general transcription factors (GTFs). These studies led to the formulation of the 'bridge' model, in which Mediator connects the transcription factor and Pol II machineries and promotes formation of the pre-initiation compl...

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

“…In line with the suggested involvement of MED13L in neural crest, 13 and consequently in the development of the facial mesenchyme, there is the presence of cleft palate in our patient 1, most likely.…”

“…Different subunits can have gene-and tissue-specific functions and several of them have already been demonstrated to be involved in neurodevelopmental processes, and to be associated to ID. 13 Specifically, heterozygous missense variants in MED13L were initially associated with dextro-looped transposition of the great arteries (dTGA), 7 while a balanced translocation t(12;17) disrupting the gene (breakpoint between exons 1 and 2) has been reported as responsible also for ID. In a large study on consanguineous families with cognitive impairment, a different homozygous missense variant was identified, but no information about the associated clinical phenotype was provided.…”

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

“…Regulation of SEs and seRNAs upon Activation of TLR4. Previous genome-wide studies have demonstrated that SEs are closely correlated with key developmental genes (12,13,39). To explore SEs and their associated genes as targets of ligand signaling, we examined the regulation of seRNAs following LPS activation of the TLR4 pathway.…”

Auxin-dependent compositional change in Mediator in ARF7- and ARF19-mediated transcription

“…auxin response | Mediator complex | CDK8 kinase module | lateral root formation M ediator is a multiprotein complex that relays integrated information from transcriptional factors to RNA polymerase II (RNAPII) (1)(2)(3). Mediator consists of ∼25-30 subunits, which are organized into three modules forming the core Mediator (head, middle, and tail) and the dissociable CDK8 kinase module (CKM) (3,4).…”

“…Email: ma-furut@agr.nagoya-u.ac.jp. 2 Present address: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.…”