A Distinct Mechanism for Coactivator versus Corepressor Function by Histone Methyltransferase G9a in Transcriptional Regulation

Purcell, Daniel J.; Jeong, Kwang Won; Bittencourt, Danielle; Gerke, Daniel S.; Stallcup, Michael R.

doi:10.1074/jbc.m111.298463

Cited by 78 publications

(84 citation statements)

References 28 publications

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“…The Ehmt1 and 2 proteins belong to the SET containing family of epigenetic regulators, 1,5 a conserved domain responsible for catalyzing lysine methylation on histones among other proteins. At the protein level, both Ehmt1 and 2 are very similar, each containing an N-terminal activation domain, 6 an Ankyrin repeat domain 7,8 and the aforementioned SET domain. Ehmt1 and Ehmt2 assemble in a stoichiometric 1:1 ratio into a larger complex and function together to regulate the mono-and dimethylation of H3K9.…”

Section: The Ehmt1/2 Complexmentioning

confidence: 99%

“…45 Ehmt2 has been shown to be essential for activation of several genes critical to early development including p21 46 and b-Globin. 47 Unlike transcriptional repression, Ehmt2's co-activator role does not require either the SET or Ank repeat domains, 6,46,48 suggesting that this coactivator role is methylation-independent. Furthermore, Ehmt2 is dependent upon a different pool of transcription factors, such as Runx2 49 and Nfe2, 47 to recruit it to sites of transcriptional activation.…”

Section: Methylation-independent Transcriptional Activating Functionsmentioning

confidence: 99%

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The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue-and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment.

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Section: The Ehmt1/2 Complexmentioning

confidence: 99%

Section: Methylation-independent Transcriptional Activating Functionsmentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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“…In addition, G9a can activate transcription of specific genes through a mechanism that does not require its methyltransferase activity (12,(16)(17)(18)(19). It is currently unclear how G9a can act to mediate both the activation and repression of transcription.…”

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confidence: 99%

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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“…Notwithstanding the current consensus on the role of G9a in regulation of transcriptional activity as a transcriptional co-repressor, recent studies have challenged this view by showing that G9a also positively regulates gene expression and thus acts as a co-activator 25,[30][31][32][33] . In this respect, G9a was recently reported as a transcriptional coactivator for Glucocorticoid Receptor (GR), by forming a molecular scaffold to recruit and facilitate binding of other co-activating proteins including GRIP1, CARM1 and p300 32,34 .…”

mentioning

confidence: 99%

“…In this respect, G9a was recently reported as a transcriptional coactivator for Glucocorticoid Receptor (GR), by forming a molecular scaffold to recruit and facilitate binding of other co-activating proteins including GRIP1, CARM1 and p300 32,34 . Interestingly, the underlying mechanism of G9a function as a positive regulator is methylation-independent, because UNC0646 (G9a-specific methyltransferase inhibitor) can not abolish this feature 34 , 30 .…”

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confidence: 99%

Human EHMT2/G9a activates p53 through methylation-independent mechanism

et al. 2016

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ABSTRACTp53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post-translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and PUMA, resulting in enhanced apoptosis and reduced colony formation. Significantly, siRNA-mediated knockdown of hG9a attenuated p53-dependent activation of PUMA. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of PUMA. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions.Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors.3

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A Distinct Mechanism for Coactivator versus Corepressor Function by Histone Methyltransferase G9a in Transcriptional Regulation

Cited by 78 publications

References 28 publications

The expanding role of the Ehmt2/G9a complex in neurodevelopment

The expanding role of the Ehmt2/G9a complex in neurodevelopment

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

Human EHMT2/G9a activates p53 through methylation-independent mechanism

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