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


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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    • "An alternative but not exclusive hypothesis is that HIRA and other subunits of the complex also have HIR complexindependent functions. Indeed, genome-wide ChIP-Seq analysis in human cells localized HIRA to several chromosomal positions that are not co-occupied by UBN1 or ASF1 (Pchelintsev et al., 2013), and roles as transcriptional corepressors have been demonstrated for UBN1 and CABIN1 (Aho et al., 2000; Jang et al., 2007). We expect that specific functions of the various Arabidopsis HIR complex subunits may be revealed only under certain growth and environmental conditions, or in particular cell types. "
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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.
    Nucleic Acids Research 09/2013; 42(1). DOI:10.1093/nar/gkt873 · 9.11 Impact Factor
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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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