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MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115024 | GEO | 2018/10/08

REPOSITORIES: GEO

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MYC interacts with the G9a histone methyltransferase to control transcriptional repression in cancer

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MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

Project description:MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

| PRJNA473533 | ENA

Homo sapiens

Project description:MYC interacts with the G9a histone methyltransferase to control transcriptional repression in cancer

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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

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

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Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer [RNA-seq]

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CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [5C]

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Gene expression profiles from mammary tissue of control mice, small K5ΔNβcat hyperplasia, large K5ΔNβcat hyperplasia and K5ΔNβcat tumor

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