The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. The E-protein HEB is alternatively spliced to generate ␣ and  isoforms. While the function of these molecules has been studied in other cell types, questions persist regarding the molecular functions of HEB proteins in skeletal muscle. Our data demonstrate that HEB␣ expression remains unchanged in both myoblasts and myotubes, whereas HEB is upregulated during the early phases of terminal differentiation. Upon induction of differentiation, a MyoD-HEB complex bound the E1 E-box of the myogenin promoter leading to transcriptional activation. Importantly, forced expression of HEB with MyoD synergistically lead to precocious myogenin expression in proliferating myoblasts. However, after differentiation, HEB␣ and HEB synergized with myogenin, but not MyoD, to activate the myogenin promoter. Specific knockdown of HEB by small interfering RNA in myoblasts blocked differentiation and inhibited induction of myogenin transcription. Therefore, HEB␣ and HEB play novel and central roles in orchestrating the regulation of myogenic factor activity through myogenic differentiation.Basic helix-loop-helix (bHLH)-containing transcription factors play an important role in directing the development of a variety of cellular lineages by regulating expression of a restricted set of tissue-specific target genes (57). The myogenic regulatory factors (MRFs) are a group of muscle-specific bHLH transcription factors, consisting of MyoD, Myf5, myogenin, and MRF4, that control skeletal muscle development (41). Genetic and expression analyses indicate that Myf5 and MyoD act as determination factors that specify muscle progenitor cell identity. Although expression of MyoD or Myf5 commits a cell to the myogenic lineage, expression of MyoD is more effective at initiating differentiation. Myogenin is induced upon differentiation and plays an important role in activating the differentiation program. MRF4 appears to have a role as a determination factor in a subset of myocytes in the early somite and as a differentiation factor in later muscle fibers (24).Transcription of muscle-specific genes is dependent upon dimer interactions between MRFs and the more ubiquitously expressed E-proteins, a process mediated by the helix-loophelix motif. The E-protein family includes the E2A gene products (E12/E47), the E2-2 gene products (ITF-2A and 2B), and the HEB gene products (HEB␣ and HEB). Dimerization is dependent upon the relative abundance of each transcription factor and/or the presence of other factors that may potentiate or inhibit dimerization. Therefore, the ability of bHLH factors to homo-or heterodimerize in a variety of combinations raises the hypothesis that regulation of dimer formation is essential for control of muscle-specific gene expression.The role of E2A in myogenesis was first postulated upon finding that MyoD was able to heterodimerize with E12 and E47 in vitro (34, 35)....
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