Automethylation of G9a and its implication in wider substrate specificity and HP1 binding

Chin, Hang Gyeong; Estève, Pierre‐Olivier; Pradhan, Mihika; Benner, Jack S.; Patnaik, Debasis; Carey, Michael; Pradhan, Sriharsa

doi:10.1093/nar/gkm726

Cited by 106 publications

(128 citation statements)

References 43 publications

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“…1A and Dataset S1). Validating our approach, G9a and GLP themselves were identified, as well as a number of previously known G9a-interacting partners, including Wiz (20), DNMT1 (21), and HP1γ (22,23). In addition, several previously unknown G9a-GLP interacting proteins, including both coactivators and corepressors, were identified, which is consistent with the dual role of G9a in regulating transcription (Fig.…”

Section: Resultssupporting

confidence: 75%

Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A

Chaturvedi

Somasundaram

Singh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Chromatin remodeling is essential for controlling the expression of genes during development. The histone-modifying enzyme G9a/KMT1C can act both as a coactivator and a corepressor of transcription. Here, we show that the dual function of G9a as a coactivator vs. a corepressor entails its association within two distinct protein complexes, one containing the coactivator Mediator and one containing the corepressor Jarid1a/KDM5A. Functionally, G9a is important in stabilizing the Mediator complex for gene activation, whereas its repressive function entails a coordinate action with the histone H3 lysine 4 (H3K4) demethylase Jarid1a for the maintenance of gene repression. The essential nature of cross-talk between the histone methyltransferase G9a and the demethylase Jarid1a is demonstrated on the embryonic E y -globin gene, where the concurrent introduction of repressive histone marks (dimethylated H3K9 and dimethylated H3K27) and removal of activating histone mark (trimethylated H3K4) is required for maintenance of gene silencing. Taken together with our previous demonstration of cross-talk between UTX and MLL2 to mediate activation of the adult β maj -globin gene, these data suggest a model where “active” and “repressive” cross-talk between histone-modifying enzymes coexist on the same multigene locus and play a crucial role in the precise control of developmentally regulated gene expression.

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Section: Resultssupporting

confidence: 75%

Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A

Chaturvedi

Somasundaram

Singh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…PCAF, p300 and TIP60 are autoacetylated, G9a can be automethylated [27] and PARP-1 can be auto-ADP-ribosylated [28]. Here, we found that hMOF is autoacetylated both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 51%

Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

et al. 2011

Cell Res

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A wide variety of nuclear regulators and enzymes are subjected to acetylation of the lysine residue, which regulates different aspects of protein functions. The MYST family histone acetyltransferase, human ortholog of MOF (hMOF), plays critical roles in transcription activation by acetylating nucleosomal H4K16. In this study, we found that hMOF acetylates itself in vitro and in vivo, and the acetylation is restricted to the conserved MYST domain (C2HC zinc finger and HAT), of which the K274 residue is the major autoacetylation site. Furthermore, the class III histone deacetylase SIRT1 was found to interact with the MYST domain of hMOF through the deacetylase catalytic region and deacetylate autoacetylated hMOF. In vitro binding assays showed that non-acetylated hMOF robustly binds to nucleosomes while acetylation decreases the binding ability. In HeLa cells, the recruitment of hMOF to the chromatin increases in response to SIRT1 overexpression and decreases after knockdown of SIRT1. The acetylation mimic mutation K274Q apparently decreases the chromatin recruitment of hMOF as well as the global H4K16Ac level in HeLa cells. Finally, upon SIRT1 knockdown, hMOF recruitment to the gene body region of its target gene HoxA9 decreases, accompanied with decrease of H4K16Ac at the same region and repression of HoxA9 transcription. These results suggest a dynamic interplay between SIRT1 and hMOF in regulating H4K16 acetylation.

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“…The related enzyme PRMT1 methylates H4R3 (31) and also modifies the PolyA-binding protein NAB2p (32). The H3K9 HMTase G9a is capable of automethylation (33). Finally, Set9 and Smyd2, the H3K4 and H3K36 HMTases, methylate distinct residues in p53, which results in opposite effects on its transcriptional activity (34,35).…”

Section: Discussionmentioning

confidence: 99%

GRIP1-associated SET-domain methyltransferase in glucocorticoid receptor target gene expression

Chinenov

Sacta

Cruz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Transcriptional regulators such as the glucocorticoid receptor (GR) recruit multiple cofactors to activate or repress transcription. Although most cofactors are intrinsically bifunctional, little is known about the molecular mechanisms dictating the specific polarity of regulation. Furthermore, chromatin modifications thought to be confined to silent loci appear in actively transcribed genes suggesting that similar enzymatic activities may mediate constitutive and transient chromatin states. GRIP1, a GR ligand-dependent coregulator of the p160 family can potentiate or inhibit transcription but the molecular contexts and mechanisms that enable GRIP1 corepressor activity are poorly understood. In a yeast 2-hybrid screen with GRIP1 repression domain (RD)-containing fragment, we repeatedly isolated the C-terminal region of a SET domain-containing protein subsequently identified as histone H4 lysine 20 trimethyltransferase, Suv4-20h1. We cloned a full-length Suv4-20h1 and dissected its interaction with GRIP1 in yeast, in vitro, and in mammalian cells. Strict nuclear localization and high salt concentration required for Suv4-20h1 extraction were consistent with its tight association with chromatin. Overexpression of Suv4-20h1 in human U2OS and A549 cells expressing integrated and endogenous GR, respectively, antagonized liganddependent induction of a subset of GR target genes, whereas Suv4-20h1 siRNA-mediated depletion had a reciprocal effect. Inhibition of GR transactivation required both the GRIP1 interacting region of Suv4-20h1 and its catalytic activity. Thus, Suv4-20h1 known exclusively as a factor involved in constitutive heterochromatin maintenance, actively participates in hormone-dependent transcriptional regulation affecting GR target gene expression in a promoter-and cell type-specific manner.

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Automethylation of G9a and its implication in wider substrate specificity and HP1 binding

Cited by 106 publications

References 43 publications

Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A

Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A

Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

GRIP1-associated SET-domain methyltransferase in glucocorticoid receptor target gene expression

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