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G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia [ChIP-seq]

ABSTRACT: Chronic hypoxia inhibits apoptosis to enhance survival of cancer cells. The mechanisms that prevent apoptosis under hypoxia are unclear. Here, we show that hypoxia induced G9a, a lysine methyltransferase, which methylates a tumor suppressor, Runt-related transcription factor 3 (RUNX3) at lysines 129 and 171. G9a-mediated methylation reduced transcriptional activity of RUNX3 by inhibiting interactions with its transcriptional cofactors, the core-binding factor-beta (CBF-beta) and p300, and also decreased the protein level of RUNX3 via Smurf1-mediated proteasomal degradation. Through ChIP-seq and gene expression profiling, G9a-mediated methylation inhibited expression of genes involved in apoptosis, thereby enhancing survival and proliferation of cancer cells both in vitro and vivo. Our results suggest G9a-dependent methylation of RUNX3 as a therapeutic target to control tumor growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124481 | GEO | 2020/11/02

REPOSITORIES: GEO

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Negative regulation of RUNX3 activity by G9a-mediated protein methylation in hypoxia [array]

Project description:Chronic hypoxia inhibits apoptosis and cell cycle arrest in cancer cells, leading to cell survival, proliferation and angiogenesis. The mechanism for anti-apoptosis and cell proliferation in hypoxic cancer cells is still elusive. Here, we showed that hypoxia inactivates Runt-related transcription factor 3 (RUNX3), which is known to play as a tumor suppressor to induce apoptosis and cell cycle arrest in various cancers. RUNX3 is methylated under hypoxic conditions at lysines (K) 129 and 171 through its interaction with methyltranferase G9a. Gene expression profiling revealed that the mutations of K129 and 171 in RUNX3 induced the expression of genes related to apoptosis and cell cycle arrest under hypoxic conditions, indicating critical roles of the RNUX methylation in anti-apoptosis and cell proliferation. Moreover, K129 and 171 mutants, compared to G9a or G9a+RUNX3 control, showed significant reduction in apoptotic ability and tumor progression in xenograft models. Therefore, G9a-dependent methylation of RUNX3 is a novel target to inhibit cell proliferation and anti-apoptosis under hypoxic conditions during tumorigenesis.

2020-11-02 | GSE81693 | GEO

G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia

Project description:G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia

| PRJNA512136 | ENA

G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia [ChIP-seq]

Project description:G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia [ChIP-seq]

| PRJNA512137 | ENA

Homo sapiens

Project description:Negative regulation of RUNX3 activity by G9a-mediated protein methylation in hypoxia [array]

| PRJNA322320 | ENA

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [Affymetrix]

Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. Microarray has been perform in triplicate on total extract RNA from mES cell (TT2 : Wildtype and KOs G9a-/-, GLP-/-, G9a-/- and GLP-/-)

2014-01-03 | E-GEOD-46544 | biostudies-arrayexpress

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [RNA-Seq]

Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. RNA-seq has been perform in triplicate on mES cell (TT2 : Wildtype, and KO G9a-/-)

2014-01-03 | E-GEOD-49669 | biostudies-arrayexpress

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [ChIP-Seq]

Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. ChIP-seq has been performed for G9a and Ezh2 in wild type TT2 mES cells or in mES cells lacking both G9a and GLP (G9a-/-GLP-/-). As a control, input DNA was saved before immunoprecipitation. Note that the two inputs (Input_TT2_0 and Input_TT2_1) have been combined and used as control for Ezh2 and G9a ChIP-seq.

2014-01-03 | E-GEOD-46536 | biostudies-arrayexpress

Histone H3K9 Methyltransferase G9a Represses PPARγ Expression and Adipogenesis [Affymetrix expression data]

Project description:PPARγ promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is enriched on the entire PPARγ locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARγ. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPARγ promoter, which promotes PPARγ expression. Interestingly, G9a represses PPARγ expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPARγ expression and facilitating Wnt10a expression, G9a represses adipogenesis. Examination of gene expression changes in G9a KO brown preadipocytes

2013-02-01 | E-GEOD-41456 | biostudies-arrayexpress

Histone H3K9 Methyltransferase G9a Represses PPAR? Expression and Adipogenesis [ChIP-Seq and RNA-Seq data]

Project description:PPAR? promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is enriched on the entire PPAR? locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPAR?. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPAR? promoter, which promotes PPAR? expression. Interestingly, G9a represses PPAR? expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPAR? expression and facilitating Wnt10a expression, G9a represses adipogenesis. Examination of 3 different histone modification changes in 3T3-L1 preadipocytes

2013-02-01 | E-GEOD-41455 | biostudies-arrayexpress

Smurf1 modulates Smad signaling pathway in fibrotic cataract formation [cell line]

Project description:Purpose: TGF-β/BMP signaling pathway has a significant role in fibrotic cataract. Smurf1, a ubiquitin protein ligase, regulates the TGF-β/BMP signaling pathway through the ubiquitin-proteasome system (UPS). This study aims to investigate the role of Smurf1 in the progression of fibrotic cataract and its underlying mechanism.Method: We employed a mouse injury-induced anterior subcapsular cataract (ASC) model and administered Smurf1 inhibitor A01 through anterior chamber injection for in vivo investigation. RNA sequencing was performed to examine global gene expression changes. The volume of the subcapsular opacity was determined using whole-mount immunofluorescence of lens anterior capsules. Lentivirus was utilized to create cell lines with Smurf1 knockdown or overexpression in SRA01/04. Protein levels were assessed by Simple Western. Lens epithelial cell (LEC) proliferation was evaluated by CCK8 and EdU assays. LEC migration was measured by Transwell and wound healing assays.Results: The mRNA levels of genes associated with cell proliferation, migration, epithelial-mesenchymal transition (EMT), TGF-β/BMP pathway and UPS, including Smurf1, were upregulated in ASC model. The mRNA expression of Smurf1 was also upregulated in anterior lens capsules of age-related cataract patients. Anterior chamber injection of A01 inhibited ASC formation and EMT. In vitro knockdown of Smurf1 resulted in reduced proliferation, TGF-β2-induced migration and EMT of LECs. Smurf1 inhibition upregulated Smad1, Smad5 and pSmad1/5. Conversely, Smurf1 overexpression displayed the opposite phenotypes.Conclusion: Smurf1 regulated the progression of fibrotic cataract by influencing the proliferation, migration and EMT of LECs through regulation of Smad signaling pathway, offering a novel target for the treatment of fibrotic cataract.

2024-02-14 | GSE245407 | GEO

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