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Gain-of-function genetic alterations of G9a drive oncogenesis II

ABSTRACT: Gain-of-function genetic alterations of G9a drive oncogenesis II

PROVIDER: PRJNA614541 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11396396_1.fastq.gz	Fastqsanger.gz
	SRR11396396_2.fastq.gz	Fastqsanger.gz
	SRR11396397_1.fastq.gz	Fastqsanger.gz
	SRR11396397_2.fastq.gz	Fastqsanger.gz
	SRR11396398_1.fastq.gz	Fastqsanger.gz

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Gain-of-function genetic alterations of G9a drive oncogenesis

Project description:Gain-of-function genetic alterations of G9a drive oncogenesis

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Gain-of-function genetic alterations of G9a drive oncogenesis I

Project description:Gain-of-function genetic alterations of G9a drive oncogenesis I

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Gain-of-function genetic alterations of G9a drive oncogenesis II

Project description:Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/b-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in ~26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrate that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations.

2020-04-20 | GSE147427 | GEO

Gain-of-function genetic alterations of G9a drive oncogenesis I

2020-04-20 | GSE147419 | GEO

Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis.

Project description:Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/?-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations. SIGNIFICANCE: Oncogenic G9a abnormalities drive tumorigenesis and the "cold" immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore "hot" tumor immune microenvironments.This article is highlighted in the In This Issue feature, p. 890.

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Gain-of-function genetic alterations of G9a drive oncogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-20 | GSE147429 | GEO

Viral integration transforms chromatin to drive oncogenesis

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Role of the histone methylase G9a in pancreatic carcinogenesis

Project description:Accumulating evidences propose the importance of epigenetic regulation in pancreatic carcinogenesis, but the mechanistic insights of a variety of histone modification process still remains to be elucidated. G9a functions as a transcriptional repressor via the methylating activity specific for histone H3 lysine9. We identified G9a as a critical factor in the development of murine pancreatic oncogenesis.

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

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.

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

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

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