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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [RNA-seq]

ABSTRACT: Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [RNA-seq]

PROVIDER: PRJNA623588 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11499104.fastq.gz	Fastqsanger.gz
	SRR11499105.fastq.gz	Fastqsanger.gz
	SRR11499106.fastq.gz	Fastqsanger.gz
	SRR11499107.fastq.gz	Fastqsanger.gz
	SRR11499108.fastq.gz	Fastqsanger.gz

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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [MeDIP-seq]

Project description:Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [MeDIP-seq]

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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [MeDIP-seq]

Project description:The de novo DNA methyltransferase Dnmt3a is mutated in human acute myeloid leukemia, and suppresses tumorigenesis in murine models of leukemia and lung cancer. Conversely, deregulation of the other de novo DNA methyltransferase, Dnmt3b, predominantly promotes tumorigenesis. However, the molecular mechanisms underlying the roles of Dnmt3a and Dnmt3b in cancer remain poorly understood. Using conditional knockout mice, here we show that Dnmt3a -- but not Dnmt3b -- strongly protects epidermal stem cells from carcinogen-induced tumor initiation, without affecting the progression of benign lesions to aggressive carcinomas. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous cell carcinomas acquired a more aggressive fate and even became metastatic, indicating that Dnmt3b is tumor-suppressive, rather than pro-tumorigenic, in epidermal neoplasia. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers, and inhibits the expression of lipid metabolism and cell proliferation genes by directly methylating their promoters. Altogether, we demonstrate that Dnmt3a, but not Dnmt3b, is critical for suppressing epidermal tumor initiation, while both enzymes prevent tumor progression.

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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [ChIP-seq]

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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [RNA-seq]

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Project description:Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [ChIP-seq]

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Dnmt3a and Dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis

Project description:Here, we show that Dnmt3a and Dnmt3b show non-overlapping and unique patterns of genomic localization in human epidermal stem cells and their differentiated counterparts. Dnmt3a, but not Dnmt3b, binds to the TSSs of a cohort of genes required for the interaction of stem cells with their underlying stroma. Unexpectedly, TSSs bound by Dnmt3a are highly transcribed and are devoid of DNA-methylation. Conversely, Dnmt3b specifically decorates the genebody of genes that establish the stem cell and differentiated signatures. Genic occupation by Dnmt3b correlates with high levels of DNA-methylation, broad domains of histone H3K4me3 8, and robust transcription. Intriguingly, both proteins also bind to the most active subset of enhancers, and are required for the production of their associated bidirectional enhancer RNAs 9. We show that typical and super-enhancers are very dynamically regulated during the linear transition of epidermal stem cells to differentiated keratinocytes. Interestingly, Dnmt3a and Dnmt3b show a strong preference for the super-enhancers that define the ectodermal lineage, but importantly, that also establish the functional traits associated to the stem cell and differentiated states. These enhancers contain very low levels of DNA-methylation, but high amounts of DNA-hydroxymethylation. Depletion of either protein completely impairs human epidermal stem cell self-renewal by inducing their spontaneous differentiation.

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Insulin receptor associates with promoters genome-wide and regulates gene expression [ChIP-seq]

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Project description:Insulin receptor associates with promoters genome-wide and regulates gene expression [RNA-seq 2]