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Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation.

ABSTRACT: Myocyte enhancer factor 2 (MEF2) is a family of transcription factors that regulates many processes, including muscle differentiation. Due to its many target genes, MEF2D requires tight regulation of transcription activity over time and by location. Epigenetic modifiers have been suggested to regulate MEF2-dependent transcription via modifications to histones and MEF2. However, the modulation of MEF2 activity by lysine methylation, an important posttranslational modification that alters the activities of transcription factors, has not been studied. We report the reversible lysine methylation of MEF2D by G9a and LSD1 as a regulatory mechanism of MEF2D activity and skeletal muscle differentiation. G9a methylates lysine-267 of MEF2D and represses its transcriptional activity, but LSD1 counteracts it. This residue is highly conserved between MEF2 members in mammals. During myogenic differentiation of C2C12 mouse skeletal muscle cells, the methylation of MEF2D by G9a decreased, on which MEF2D-dependent myogenic genes were upregulated. We have also identified lysine-267 as a methylation/demethylation site and demonstrate that the lysine methylation state of MEF2D regulates its transcriptional activity and skeletal muscle cell differentiation.

SUBMITTER: Choi J

PROVIDER: S-EPMC3874188 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation.

Choi Jinmi J Jang Hyonchol H Kim Hyunsoo H Lee Jong-Hyuk JH Kim Seong-Tae ST Cho Eun-Jung EJ Youn Hong-Duk HD

Nucleic acids research 20130927 1

Myocyte enhancer factor 2 (MEF2) is a family of transcription factors that regulates many processes, including muscle differentiation. Due to its many target genes, MEF2D requires tight regulation of transcription activity over time and by location. Epigenetic modifiers have been suggested to regulate MEF2-dependent transcription via modifications to histones and MEF2. However, the modulation of MEF2 activity by lysine methylation, an important posttranslational modification that alters the acti ...[more]

PMID: 24078251

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Project description:Myocyte differentiation involves complex interactions between signal transduction pathways and transcription factors. The estrogen-related receptors (ERRs) regulate energy substrate uptake, mitochondrial respiration, and biogenesis and may target structural gene programs in striated muscle. However, ERR?'s role in regulating myocyte differentiation is not known. ERR? and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) are coordinately upregulated with metabolic and skeletal muscle-specific genes early in myogenesis. We analyzed effects of ERR? overexpression and loss of function in myogenic models. In C2C12 myocytes ERR? overexpression accelerated differentiation, whereas XCT790 treatment delayed myogenesis and resulted in myotubes with fewer mitochondria and disorganized sarcomeres. ERR?-/- primary myocytes showed delayed myogenesis, resulting in structurally immature myotubes with reduced sarcomeric assembly and mitochondrial function. However, sarcomeric and metabolic gene expression was unaffected or upregulated in ERR?-/- cells. Instead, ERR?-/- myocytes exhibited aberrant ERK activation early in myogenesis, consistent with delayed myotube formation. XCT790 treatment also increased ERK phosphorylation in C2C12, whereas ERR? overexpression decreased early ERK activation, consistent with the opposing effects of these treatments on differentiation. The transient induction of MAP kinase phosphatase-1 (MKP-1), which mediates ERK dephosphorylation at the onset of myogenesis, was lost in ERR?-/- myocytes and in XCT790-treated C2C12. The ERR?-PGC-1? complex activates the Dusp1 gene, which encodes MKP-1, and ERR? occupies the proximal 5' regulatory region during early differentiation in C2C12 myocytes. Finally, treatment of ERR?-/- myocytes with MEK inhibitors rescued normal ERK signaling and myogenesis. Collectively, these data demonstrate that ERR? is required for normal skeletal myocyte differentiation via modulation of MAP kinase signaling.

Dataset Information

Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation.

Publications

Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation.

Similar Datasets

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