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G9a/GLP-sensitivity of H3K9me2 Demarcates Two Types of Genomic Compartments.

ABSTRACT: In the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike in mouse embryonic stem cells, inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modifications was strongly associated with B-type (inactive) genomic compartments. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to decreased chromatin-nuclear lamina interactions mainly at G9a/GLP-sensitive regions, increased degree of genomic compartmentalization, and up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.

SUBMITTER: Yan Z

PROVIDER: S-EPMC8242262 | biostudies-literature |

REPOSITORIES: biostudies-literature

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G9a/GLP-dependent H3K9me2 patterning alters chromatin structure at CpG islands in hematopoietic progenitors.

Project description:BackgroundThe formation of chromatin domains is an important step in lineage commitment. In human hematopoietic stem and progenitor cells (HSPCs), G9a/GLP-dependent H3K9me2 chromatin territories form de novo during lineage specification and are nucleated at punctate sites during lineage commitment. Here, we examined the patterning of G9a/GLP-dependent H3K9me2 in HSPCs and the consequences for chromatin structure.ResultsWe profiled chromatin accessibility across the genome of HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO. We observed that chromatin accessibility is dramatically altered at the regions of H3K9me2 nucleation. We have characterized the regions of H3K9me2 nucleation, with our analysis revealing that H3K9me2 is nucleated in HSPCs at CpG islands (CGIs) and CGI-like sequences across the genome. Our analysis furthermore revealed a bias of H3K9me2 nucleation towards regions with low rates of C- > T deamination, which typically lack DNA methylation. Lastly, we examined the interaction of H3K9me2 and DNA methylation and determined that chromatin accessibility changes upon loss of H3K9me2 are dependent on the presence of DNA methylation.ConclusionsThese results indicate that H3K9me2 nucleation is established at specific sequences that have base composition similar to CGIs. Our results furthermore indicate that H3K9me2 nucleation leads to local changes in chromatin accessibility and that H3K9me2 and DNA methylation work synergistically to regulate chromatin accessibility.

| S-EPMC4166411 | biostudies-literature

G9a/GLP-dependent H3K9me2 patterning alters chromatin structure at CpG islands in hematopoietic progenitors.

Project description:We profiled chromatin accessibility across the genome of HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO. We observed that chromatin accessibility is dramatically altered at the regions of H3K9me2 nucleation. We have characterized the regions of H3K9me2 nucleation, revealing that H3K9me2 is nucleated in HSPCs at CpG islands (CGIs) and CGI-like sequences across the genome. Our analysis furthermore revealed a bias of H3K9me2 nucleation towards regions with low rates of C->T deamination, which typically lack DNA methylation. Lastly we examined the interaction of H3K9me2 and DNA methylation and determined that chromatin accessibility changes upon loss of H3K9me2 are dependent on the presence of DNA methylation. Examination of chromatin remodeling with FAIRE-seq in HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO

2014-09-25 | E-GEOD-59749 | biostudies-arrayexpress

G9a/GLP-dependent H3K9me2 patterning alters chromatin structure at CpG islands in hematopoietic progenitors.

2014-09-25 | GSE59749 | GEO

H3K9 methyltransferase G9a and the related molecule GLP.

Project description:The discovery of Suv39h1, the first SET domain-containing histone lysine methyltransferase (HKMT), was reported in 2000. Since then, research on histone methylation has progressed rapidly. Among the identified HKMTs in mammals, G9a and GLP are the primary enzymes for mono- and dimethylation at Lys 9 of histone H3 (H3K9me1 and H3K9me2), and exist predominantly as a G9a-GLP heteromeric complex that appears to be a functional H3K9 methyltransferase in vivo. Recently, many important studies have reported that G9a and GLP play critical roles in various biological processes. The physiological relevance of G9a/GLP-mediated epigenetic gene regulation is discussed.

| S-EPMC3078703 | biostudies-literature

SPOP mutation induces DNA methylation via stabilizing GLP/G9a.

Project description:Mutations in SPOP E3 ligase gene are reportedly associated with genome-wide DNA hypermethylation in prostate cancer (PCa) although the underlying mechanisms remain elusive. Here, we demonstrate that SPOP binds and promotes polyubiquitination and degradation of histone methyltransferase and DNMT interactor GLP. SPOP mutation induces stabilization of GLP and its partner protein G9a and aberrant upregulation of global DNA hypermethylation in cultured PCa cells and primary PCa specimens. Genome-wide DNA methylome analysis shows that a subset of tumor suppressor genes (TSGs) including FOXO3, GATA5, and NDRG1, are hypermethylated and downregulated in SPOP-mutated PCa cells. DNA methylation inhibitor 5-azacytidine effectively reverses expression of the TSGs examined, inhibits SPOP-mutated PCa cell growth in vitro and in mice, and enhances docetaxel anti-cancer efficacy. Our findings reveal the GLP/G9a-DNMT module as a mediator of DNA hypermethylation in SPOP-mutated PCa. They suggest that SPOP mutation could be a biomarker for effective treatment of PCa with DNA methylation inhibitor alone or in combination with taxane chemotherapeutics.

| S-EPMC8481544 | biostudies-literature

H3K9me2 regulation of BDNF expression via G9a partakes in the progression of heart failure.

Project description:BackgroundHeart disease is a major cause of mortality in developed countries. The associated pathology is mainly characterized by the loss of cardiomyocytes that contributes to heart failure (HF). This study aims to investigate the mechanism of euchromatic histone lysine methyltransferase 2 (EHMT2, also term G9a) in HF in rats.MethodsDifferentially expressed mRNAs in HF were screened using GEO database. Sera from subjects with or without HF were collected, and PCR was performed to detect the G9a expression. G9a was downregulated in cardiomyocytes exposed to oxygen-glucose deprivation (OGD), followed by CCK8, flow cytometry, colorimetric method, and western blot assays. Established HF rats were delivered with lentiviral vectors carrying sh-G9a, and TTC staining, HE staining, TUNEL, ELISA, and western blot were performed. The regulation of G9a on the downstream target BDNF was investigated by RT-qPCR, Western blot, and ChIP-qPCR. Finally, rescue experiments were carried out to substantiate the effect of G9a on cardiomyocyte apoptosis and injury via the BDNF/TrkB axis.ResultsG9a was overexpressed, whereas BDNF was downregulated in HF. Knockdown of G9a inhibited apoptosis and injury in OGD-treated cardiomyocytes and attenuated the extent of HF and myocardial injury in rats. Silencing of G9a promoted BDNF transcription by repressing H3K9me2 modification of the BDNF promoter. Further depletion of BDNF partially reversed the effect of sh-G9a in alleviating cardiomyocyte apoptosis and injury by inhibiting the TrkB signaling pathway.ConclusionG9a inhibits BDNF expression through H3K9me2 modification, thereby impairing the TrkB signaling pathway and exacerbating the development of HF.

| S-EPMC9020036 | biostudies-literature

Inhibition of H3K9me2-specific histone methyltransferase, G9a/GLP, reveals transcripts regulated by the establishment of H3K9me2 in hematopoietic stem and progenitor cells

Project description:We have performed RNA-seq from DMSO control treated, G9a/GLP inhibitor (UNC0638) treated, and DNA-demethylating agent (Decitabine) treated CD34+ hematopoietic stem and progenitor cells. This experiment was performed to identify transcripts that were uniquely affected by the loss of H3K9me2 in hematopoietic stem and progenitor cells.

2023-05-01 | GSE204743 | GEO

The genomic distribution of G9a, H3K9me2 and H3K27me3 in cardiac hypertrophy.

Project description:The role of the histone methyltrasferase G9a (also known as Ehmt2) in the normal heart has not been studied extensively. To identify which genes were direct targets of G9a in hypertrophic cardiomyocytes, we performed ChIP-seq for G9a and H3K9me2 – the main histone methylation catalysed by the HMT – on cardiomyocytes isolated from normal mice (sham) and mice subject to transverse aortic constriction (TAC) for 1 wk, a surgical procedure that causes cardiac hypertrophy following the induction of pressure overload. We considered the best G9a-bound genomic regions as those in which G9a and H3K9me2 peaks overlapped. Since G9a contributes to trimethylation of H3K27 at a set of developmental genes through its interaction with PRC2, we also evaluated whether G9a had an effect on the distribution of this histone mark in hypertrophic cardiomyocytes. To this end, we performed ChIP-seq for H3K27me3 in CMs isolated from sham and TAC mice.

2017-08-30 | GSE93752 | GEO

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors.

Project description:Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.

| S-EPMC5562403 | biostudies-literature

G9a and Glp methylate lysine 373 in the tumor suppressor p53.

Project description:The tumor suppressor p53 is regulated by numerous post-translational modifications. Lysine methylation has recently emerged as a key post-translational modification that alters the activity of p53. Here, we describe a novel lysine methylation site in p53 that is carried out by two homologous histone methyltransferases, G9a and Glp. G9a and Glp specifically methylate p53 at Lys(373), resulting mainly in dimethylation. During DNA damage, the overall level of p53 modified at Lys(373)me2 does not increase, despite the dramatic increase in total p53, indicating that Lys(373)me2 correlates with inactive p53. Further, reduction of G9a and/or Glp levels leads to a larger population of apoptotic cells. Examination of the Oncomine data base shows that G9a and Glp are overexpressed in various cancers compared with corresponding normal tissues, suggesting that they are putative oncogenes. These data reveal a new methylation site within p53 mediated by the methylases G9a and Glp and indicate that G9a is a potential inhibitory target for cancer treatment.

| S-EPMC2843213 | biostudies-literature

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