MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA473533 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7229800_1.fastq.gz | Fastqsanger.gz | |||
| SRR7229800_2.fastq.gz | Fastqsanger.gz | |||
| SRR7229801_1.fastq.gz | Fastqsanger.gz | |||
| SRR7229801_2.fastq.gz | Fastqsanger.gz | |||
| SRR7229802_1.fastq.gz | Fastqsanger.gz |
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Project description:MYC is an oncogenic driver that regulates transcriptional activation and repression, yet molecular mechanisms of MYC transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression to antagonize cellular transformation. By identifying the MYC Box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. In breast cancer, anti-proliferative sensitivity to G9a pharmacological inhibition associates with MYC sensitivity and the basal subtype. Inhibiting G9a in vivo suppresses MYC-dependent basal breast tumor growth. Our findings reveal G9a as an epigenetic regulator of MYC-mediated transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.
2018-10-08 | GSE115024 | GEO
Project description:MYC is a master regulator of transcriptional activation and repression that mediates diverse physiological and disease functions, including hematopoiesis, aging, and oncogenesis, yet its essential co-regulators remain unclear. We demonstrate that MYC interacts with and regulates the G9a H3K9 methyltransferase complex to control transcriptional repression in cancer. Inhibiting G9a hinders MYC binding, shifts repressive epigenetic locales to an active state, and de-represses gene expression to antagonize MYC-dependent cellular processes. MYC requires MYC Box II region for its interaction with G9a, providing a mechanism for this region essential for transcriptional repression. In treatment models of MYC-dependent basal breast cancer, genetically inhibiting G9a decreases tumour growth. Anti-proliferative sensitivity to G9a small molecule inhibitors correlates with sensitivity to MYC knockdown and associates with the basal subtype. Our findings illustrate an epigenetic model of MYC-mediated transcriptional repression in driving oncogenesis and establishes G9a as a therapeutic vulnerability in MYC-driven cancers.
2018-10-08 | GSE100335 | GEO
Project description:We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of certain m6A-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous “G9a-translated” proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
2023-10-20 | PXD044382 | Pride
Project description:We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of certain m6A-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous “G9a-translated” proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
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Project description:Posttranslational modifications of histone N-terminal tails influence the status of chromatin and eventually control the transcriptional outcome of a particular gene. As a histone H3K9 methyltransferase (HMTase) in higher eukaryotes, G9a-mediated transcriptional repression is the major epigenetic silencing machinery. UHRF1 (ubiquitin-like with PHD and ring finger domains I) binds to hemi-methylated DNA and plays essential role in maintenance of DNA methylation by recruiting DNMT1. Here, we provide evidence that UHRF1 is transcriptionally downregulated by H3K9 HMTase G9a. We found that increased expression of G9a along with transcription factor YY1 specifically represses UHRF1 transcription. We uncovered showed that G9a regulates UHRF1-mediated H3K23 ubiquitylation and proper DNA replication maintenance by FACS analysis and propose that H3K9 HMTase G9a is a specific epigenetic regulator of UHRF1.
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Project description:Whereas DNA methylation is essential for genomic imprinting, the importance of histone methylation in the allelic repression of imprinted genes is unclear. âImprinting control regionsâ (ICRs), however, are consistently marked by histone H3 K9 methylation on their DNA-methylated allele. In the placenta, the paternal silencing along the Kcnq1 domain on distal chromosome 7 also correlates with the presence of H3-K9 methylation, but imprinted repression at these genes is maintained independently of DNA methylation. To explore which histone methyltransferase (HMT) could mediate the allelic H3-K9 methylation on distal chromosome 7, and at ICRs, we generated mouse conceptuses deficient for the SET-domain protein G9a. We find that in the embryo and placenta, the differential DNA methylation at ICRs and imprinted genes is maintained in the absence of G9a. Accordingly, in embryos, imprinted gene expression is unchanged at the domains analysed, in spite of a global loss of H3-K9 di-methylation (H3K9me2). In contrast, the placenta-specific imprinting of genes on distal chromosome 7 is lost in the absence of G9, and this correlates with a loss of H3K9me2 and H3K9me3. These findings provide the first in vivo evidence for the involvement of a SET domain protein in imprinting and highlight the importance of histone lysine methylation rather than DNA methylation in the maintenance of imprinting in the trophoblast lineage. Experiment Overall Design: Number of samples: four (two biologically replicate G9a-/- pooled placentae samples, and two biologically replicate wildtype pooled placentae samples). The first G9a-/- and wildtype replicates were used to hybridize Affymetrix MOE430A and MOE430B arrays (four arrays total). The second replicates were used to hybridize Affymetrix Mouse430_2 arrays (two arrays total).
2008-04-10 | E-GEOD-7674 | biostudies-arrayexpress
Project description:PALI1 is a newly identified accessory protein of the Polycomb Repressive Complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators induced upon cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.
2022-12-12 | GSE175697 | GEO
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
Project description:PALI1 is a newly identified accessory protein of the Polycomb Repressive Complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators induced upon cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.
2022-12-12 | GSE175696 | GEO
Project description:PALI1 is a newly identified accessory protein of the Polycomb Repressive Complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators induced upon cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.
2022-12-12 | GSE212625 | GEO