Cooperative Transcriptional Activation by the Neurogenic Basic Helix-Loop-Helix Protein MASH1 and Members of the Myocyte Enhancer Factor-2 (MEF2) Family

Abstract

Recent studies suggest that there are parallels between the mechanisms that regulate differentiation in the myogenic and neurogenic lineages (1). Formation of skeletal muscle is controlled by a family of myogenic basic helix-loop-helix (bHLH) 1 proteins, MyoD, myogenin, Myf5, and MRF4, which are expressed specifically in skeletal muscle and can activate the complete program for skeletal muscle differentiation when expressed in several non-muscle cell types (2). Similarly, the formation of central and peripheral neurons in Drosophila has been shown to be controlled by the achaete-scute family of bHLH factors, which are expressed in neuronal precursors and differentiated neurons (1). Two mammalian achaete-scute homologs (MASH) have been identified (3). One of these factors, MASH1, is expressed in subsets of cells in the peripheral and central nervous systems and is required for the formation of the peripheral nervous system during mouse embryogenesis (4 -6). Cell type-specific bHLH proteins like the myogenic and neurogenic factors form heterodimers with a family of ubiquitous bHLH factors known as E proteins, which includes the products of the E2A gene, E12 and E47, HEB, and the Drosophila daughterless gene product (7-9). These heterodimers bind the E box consensus sequence, CANNTG, which is found in the control regions of numerous muscle-specific genes, as well as other cell type-specific genes (7).Myogenic bHLH proteins activate muscle-specific transcription in collaboration with members of the myocyte-enhancer factor-2 (MEF2) family of transcription factors (10). There are four vertebrate mef2 genes, mef2a, mef2b, mef2c, and mef2d (11-17), whose products bind as homo-and heterodimers to an A/T-rich DNA consensus sequence associated with numerous muscle-specific genes (18). MEF2 proteins are members of the MADS (MCM1-Agamous-Deficiens-serum response factor) family of transcription factors. The MADS domain and the adjacent MEF2 domain encompass the first 86 amino acids, and together these domains mediate DNA binding and dimerization (10). Recent studies have shown that members of the MEF2 family interact directly with heterodimers formed between myogenic bHLH proteins and E proteins and that the DNA binding and dimerization domains of these two different classes of transcription factors mediate this interaction (19,20). In addition to being expressed in differentiated muscle cells, members of the MEF2 family are expressed in the developing brains of vertebrates in specific patterns that correlate with neuronal differentiation (13,21,22). Similarly, the single mef2 gene in Drosophila, D-mef2, is expressed in developing muscle and in the central and peripheral nervous systems (23).Like differentiating skeletal muscle cells, differentiating neurons exit the cell cycle irreversibly and up-regulate an array of tissue-specific genes. Given the high levels of MEF2 expression in differentiated neurons and the similar roles of bHLH proteins in specifying myogenic and neurogenic cell fates, we examined whether MEF2 factors...

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

“…The conserved MEF2A gene MEF2 element described here indicates one mechanism by which this can occur, as myogenic bHLH factors, including MyoD, are understood to control transcription of target genes through direct interactions with DNA-bound MEF2 factors (6,53). Although it remains for us to directly examine the function of the two conserved E boxes in the upstream "E" MEF2A regulatory region, these are also likely to play a role in the control of MEF2A expression by myogenic and neurogenic bHLH factors (48,53,61). It should be noted that there are multiple additional sequences in the human MEF2A regulatory region that conform to the E box consensus, but only the two sites described are conserved in sequence and location among mammalian MEF2A genes.…”

“…8 MEF2 and myogenic or neurogenic bHLH factors are known to synergize in two fundamental ways. As described above, a member of one class can use a member of the other as DNAbound scaffolding, allowing regulation of target genes of the scaffolding component (53,61). A second mechanism for cooperative control involves cross-regulation of MEF2 and myogenic bHLH factor gene promoters.…”

“…To our knowledge, there are no previous reports of a MEF2 element at a TSS. However, implementation of cap-trapper (45) and other improved cDNA library construction strategies has revealed the full 5Ј extent of many mRNAs, and we have found proteins bind the MEF2 element but also interact with DNA-bound myogenic and neurogenic bHLH factors (53,61) and Sp1 (49). p38 phosphorylates MEF2A to stimulate trans-activity (51, 75) but also targets PGC-1␣, a MEF2 co-activator (8,55).…”

Myocyte Enhancer Factor 2C as a Neurogenic and Antiapoptotic Transcription Factor in Murine Embryonic Stem Cells

“…The expression of the bHLH (basic helix-loop-helix) transcription factor Mash1 is considered to be important in determining whether neural progenitors ultimately generate neurons or glia (Parras et al, 2002;Murray et al, 2003). MASH1 was reported to regulate the expression of specific genes that are critical for neuronal differentiation via a cooperative interaction with members of the MEF2 family of transcription factors (Black et al, 1996;Mao and Nadal-Ginard, 1996). Two days after plating in FGF2 plus EGF-containing medium, the proneuronal gene MASH1 was highly expressed in virtually all MEF2CA-ESC-derived neural progenitor cells, but in many fewer control cells (Fig.…”

Mechanism for Nucleocytoplasmic Shuttling of Histone Deacetylase 7

“…In contrast, class II histone deacetylases, HDAC4 and HDAC5, repress MEF2 activity through direct physical interaction (18,(33)(34)(35)(36). In addition, a number of other transcription factors including MyoD have been shown to play a role in regulating MEF2 activity through direct association (37)(38)(39)(40)(41). During muscle differentiation, MEF2 proteins activate the expression of many muscle-specific genes.…”