MEF2: a central regulator of diverse developmental programs

Abstract

The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control cell differentiation and organogenesis. The spectrum of genes activated by MEF2 in different cell types depends on extracellular signaling and on co-factor interactions that modulate MEF2 activity. Recent studies have revealed MEF2 to form an intimate partnership with class IIa histone deacetylases, which together function as a point of convergence of multiple epigenetic regulatory mechanisms. We review the myriad roles of MEF2 in development and the mechanisms through which it couples developmental, physiological and pathological signals with programs of cell-specific transcription. IntroductionThe formation of specialized cell types and their integration into different tissues and organs during development requires the interpretation of extracellular signals by components of the transcriptional apparatus and through the subsequent activation of cascades of regulatory and structural genes by combinations of widely expressed and cell type-restricted transcription factors. The myocyte enhancer factor 2 (MEF2) transcription factor plays central roles in the transmission of extracellular signals to the genome and in the activation of the genetic programs that control cell differentiation, proliferation, morphogenesis, survival and apoptosis of a wide range of cell types.Recent studies in mice and fruit flies have revealed upstream signaling systems that control MEF2 expression and activity, and downstream effector genes that mediate the actions of MEF2 throughout development, as well as in adult tissues. These studies point to MEF2 having a central role as a mediator of epigenetic regulatory mechanisms that involve changes in chromatin configurations and the modulation of microRNAs. Here we review the mechanisms that govern MEF2 activity and discuss commonalities in the functions of MEF2 as a regulator of differentiation of diverse cell types. The requirement of MEF2 for the differentiation of seemingly unrelated cell types from multiple lineages points to MEF2 being a key component of the regulatory codes that are required for metazoan development.The MEF2 family MEF2 proteins belong to the evolutionarily ancient MADS (MCM1, agamous, deficiens, SRF) family of transcription factors (Shore and Sharrocks, 1995). Saccharomyces cerevisiae, Drosophila and Caenorhabditis elegans possess a single Mef2 gene, whereas vertebrates have four -Mef2a, b, c and d. The N-termini of MEF2 factors contain a highly conserved MADS-box and an immediately adjacent motif termed the MEF2 domain ( Fig. 1), which together mediate dimerization, DNA binding, and co-factor interactions (Black and Olson, 1998;McKinsey et al., 2002a). The C-terminal regions of MEF2 proteins, which function as transcriptional activation domains, are subject to complex patterns of alternative splicing and are divergent among family members (Fig. 1).MEF2 proteins bind to the consensus DNA sequence YTA(A/T) 4 TAR as homo-or heterodimers (Andres e...

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…In mammals, MEF2 proteins are encoded by four genes MEF2A, B, C, and D. The four MEF2 isoforms are expressed in overlapped, however, with different patterns, both in the tissues of embryos and adults (Potthoff and Olson 2007). MEF2C is more widely expressed and regulates diverse transcriptional events such as the development and differentiation of many tissues (Potthoff and Olson 2007).…”

“…In mammals, MEF2 proteins are encoded by four genes MEF2A, B, C, and D. The four MEF2 isoforms are expressed in overlapped, however, with different patterns, both in the tissues of embryos and adults (Potthoff and Olson 2007). MEF2C is more widely expressed and regulates diverse transcriptional events such as the development and differentiation of many tissues (Potthoff and Olson 2007). In addition, MEF2C is found to be highly expressed in B cells of the spleen and lymph node (Swanson et al 1998), and plays a critical role in B cell proliferation upon antigen stimulation (Khiem et al 2008;Wilker et al 2008).…”

Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration

“…MRFs consist of MyoD, Myf5, MRF4, and myogenin, all being members of the basic helix-loop-helix (bHLH) family of proteins [4][5][6], while MEF2s consist of MEF2A, MEF2B, MEF2C, and MEF2D that belong to the MADS box family of proteins [7,8]. MRFs preferentially pair with the ubiquitously expressed E proteins (e.g., E12/E47) that also belong to the bHLH family, in order to efficiently bind to a consensus site (i.e., CANNTG, also called an E box) in the regulatory regions of many muscle-specific genes [9,10].…”

Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7

“…Phosphorylation of a series of conserved serine residues in the N-terminal regulatory domain of class IIa HDACs by calcium/calmodulin-dependent kinase (CaMK) and PKD creates docking sites for 14-3-3 chaperone proteins, which drives these HDACs from the nucleus to the cytoplasm and derepresses gene expression (11)(12)(13)(14). The MEF2 transcription factor is a key downstream target for repression by class IIa HDACs and for signal-dependent transcription in response to signaling pathways that promote class IIa HDAC phosphorylation (15).…”