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

Abstract

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.

Physical and Functional Interactions between the Histone H3K4 Demethylase KDM5A and the Nucleosome Remodeling and Deacetylase (NuRD) Complex

“…Therefore, it is possible that KDM1A and KDM5A associate with the NuRD complex in a chromatin context-dependent manner. Another study showed that KDM5A physically interacts with the H3K9 methyltransferase G9a in murine erythroid cells and functions cooperatively to repress embryonic ␤-globin gene expression (50). Although neither G9a nor its partner GLP was detected in our KDM5A complexes (Fig.…”

The expanding role of the Ehmt2/G9a complex in neurodevelopment

“…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. Once recruited Ehmt2 in turn functions as a scaffold protein to enhance recruitment of further co-activators including Carm1, 45 p300, 48 the mediator complex 14 and DNA Pol II. 47 In contrast, Ehmt1 has also been recently implicated in transcriptional activation during adipogenesis independent of Ehmt2.…”

“…9 The molecular mechanisms that target the Ehmt1/2 complex to unmethylated chromatin sites is not well defined, but may ultimately rely on physical association with auxiliary cofactor proteins such as the zinc finger-containing proteins Wiz 10,11 and Znf518, 12 or in some cases non-coding RNA. 13 Once recruited, to exert its repressive effects the Ehmt1/2 complex functions with co-repressors such as H3K4 demethylase Jarid1a, 14 the histone deacetylase Hdac1, [15][16][17] the heterochromatin promoting HP1 18,19 and various DNMTs. [20][21][22] We, and others, have recently identified an additional cofactor necessary for proper ehmt1/2 recruitment to target genes: znf644.…”

Human EHMT2/G9a activates p53 through methylation-independent mechanism

“…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 .…”