Gene programs regulated by MEF2 transcription factors in rodent striated muscle cells
Estrella, Nelsa Leonor
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Transcriptional programs regulating myogenesis are multi-layered, requiring carefully orchestrated temporal activation of a wide range of myogenic transcription factors for proper muscle formation. The MEF2 transcription factor family is required for muscle differentiation, however the roles of individual mammalian MEF2 isoforms, MEF2A, -B, -C, and -D, in this process has not been thoroughly investigated. Acute knockdown of individual MEF2 isoforms in skeletal myoblasts revealed that MEF2A is required for myogenesis in vitro, whereas MEF2B, -C, and -D are dispensable for this process. Microarray analysis performed on myotubes depleted of each MEF2 isoform revealed that MEF2 factors regulate distinct gene programs in skeletal muscle. Moreover, computational analysis of the upstream regulatory regions of MEF2 isoform-dependent genes uncovered a distinct complement of transcription factor binding sites suggesting potential co-factor interactions in muscle gene regulation. Whereas all four MEF2 family members are expressed in adult skeletal muscle, MEF2A and MEF2D are the major isoforms expressed in the post-natal heart. Previous studies in cardiomyocytes have demonstrated that MEF2A regulates genes encoding proteins localized to the costamere, an essential macromolecular complex required for proper muscle contraction. By contrast, genome-wide expression analysis suggests a role for MEF2D in cardiomyocyte cell cycle regulation. MEF2D- deficient cardiomyocytes up-regulate a subset of positive cell cycle regulators and display activation of the PI3K/AKT signaling pathway. Furthermore, MEF2D-depleted cardiomyocytes have increased levels of cytoplasmic FOXO3a, a cell cycle inhibitor and direct AKT target. Along these lines, MEF2D-depleted cardiomyocytes have decreased levels of the PI3K/AKT repressor PTEN. Analysis of the Pten promoter revealed a highly conserved MEF2 site, which is required for activation of this promoter by MEF2D. Taken together, these findings demonstrate that MEF2D modulates PI3K/AKT activation through transcriptional regulation of the tumor suppressor PTEN. In the absence of MEF2D, aberrant activation of the cell cycle ultimately results in cardiomyocyte cell death. These results demonstrate that MEF2 family members regulate distinct gene programs required for proper skeletal and cardiac muscle function.
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