Article

Cabin1 Represses MEF2 Transcriptional Activity by Association with a Methyltransferase, SUV39H1

Sungkyunkwan University, Sŏul, Seoul, South Korea
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2007; 282(15):11172-9. DOI: 10.1074/jbc.M611199200
Source: PubMed

ABSTRACT

Myocyte enhancer factor 2 (MEF2) plays pivotal roles in various biological processes, and its transcriptional activity is regulated by histone acetylation/deacetylation enzymes in a calcium-dependent fashion. A calcineurin-binding protein 1 (Cabin1) has been shown to participate in repression of MEF2 by recruiting mSin3 and its associated histone deacetylases. Here, we report that histone methylation also takes a part in Cabin1-mediated repression of MEF2. Immunoprecipitate of Cabin1 complex can methylate histone H3 by association with SUV39H1. SUV39H1 increased Cabin1-mediated repression of MEF2 transcriptional activity in MEF2-targeting promoters. The SUV39H1 was revealed to bind to the 501-900-amino acid region of Cabin1, which was distinct from its histone deacetylase-recruiting domain. In addition, the Gal4-Cabin1-(501-900) alone repressed a constitutively active Gal4-tk-promoter, indicating that Cabin1 recruits SUV39H1 and represses transcriptional activity. Finally, both SUV39H1 and Cabin1 were shown to bind on the MEF2 target promoter in a calcium-dependent manner. Thus, Cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress MEF2 transcriptional activity.

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    • "Thus, to modulate MEF2 activity and effect its precise regulation of target genes, corepressors and coactivators are recruited to MEF2 target promoters. Calcineurin-binding protein-1 (Cabin1) recruits histone methyltransferases and deacetylases, such as Suv39h1 and HDACs, to repress MEF2 activity through chromatin remodeling (12–16).The histone demethylase LSD1 and acetyltransferase p300 activate MEF2 transcriptional activity by modifying the histones in MEF2 target promoters (17,18). Moreover, a histone chaperone, HIRA, in cooperation with Asf1, stimulates MEF2 transcriptional activity during muscle differentiation (19). "
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    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.
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    • "For differentiation of C2C12 cells into myotubes, GM was replaced by media containing 2–5% horse serum with antibiotics (differentiation medium, DM). HEK293 cells were described previously [7] and were transfected using the calcium phosphate coprecipitation methods or Welfect-EX™ PLUS reagent (WelGENE, Korea). "
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    ABSTRACT: During myogenesis, transcriptional activities of two major myogenic factors, MyoD and myocyte enhancer factor 2 (Mef2) are regulated by histone modifications that switch on and off the target genes. However, the transition mechanism from repression to activation modes of histones has not been defined. Here we identify that lysine specific demethylase 1, (LSD1) is responsible for removing the repressive histone codes during C2C12 mouse myoblast differentiation. The potent role of LSD1 is suggested by the increment of its expression level during myogenic differentiation. Moreover, by performing co-immunoprecipitation and ChIP assay, physically interaction of LSD1 with MyoD and Mef2 on the target promoters was identified. Their interactions were resulted in upregulation of the transcription activities shown with increased luciferase activity. Interruption of demethylase activity of LSD1 using shRNA or chemical inhibitor, pargyline, treatment led to aberrant histone codes on myogenic promoters during skeletal muscle differentiation. We also demonstrate that inhibition of LSD1 impairs C2C12 mouse myoblast differentiation. Our results show for the first time the regulatory mechanism of myogenesis involving histone demethylase. Altogether, the present study suggests a de-repression model and expands the understanding on the dynamic regulation of chromatin during myogenesis.
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    • "CNS defects could provide a major contribution. The repressive action of Cabin1 on calcineurin in both the mature CNS (Lai et al., 2000) and immune system (Jang et al., 2007a) and on MEF2 in the immune system (Sun et al., 1998; Youn et al., 1999; Han et al., 2003; Pan et al., 2005; Jang et al., 2007b) leave open the possibility that Cabin1 repression of these pathways also plays a broad role during the development of both tissues. In T-cells, Cabin1 acts as a repressor of calcineurin and MEF2 under normal conditions, but repression is alleviated in response to elevated levels of intracellular calcium (Youn et al., 1999). "
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    ABSTRACT: Nervous system assembly and function depends on precise regulation of developmental gene expression. Cabin1, an essential gene in developing mice, is enriched in regions of the developing zebrafish central nervous system (CNS). Cabin1 is a repressor of MEF2- (myocyte enhancer factor 2) and calcineurin-mediated transcription in the immune system, but its function in the CNS during development is unknown. We identified Cabin1 from a library of genes enriched in developing neurons and determined the temporal and spatial expression of Cabin1 mRNA during CNS development. We found Cabin1 mRNA expression in the developing brain at times correlated with later aspects of neuronal differentiation. In some regions of the CNS Cabin1 expression overlaps with regions that also express proteins known to interact with Cabin1: MEF2 and/or calcineurin. We suggest that Cabin1 could act as a regulator of MEF2 and calcineurin activity in the developing nervous system, given their roles in neuronal differentiation and synaptic refinement.
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