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DNA methylation regulates haematopoietic development

ABSTRACT: DNA methylation regulates haematopoietic development

PROVIDER: PRJNA703974 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13764220_1.fastq.gz	Fastqsanger.gz
	SRR13764220_2.fastq.gz	Fastqsanger.gz
	SRR13764221_1.fastq.gz	Fastqsanger.gz
	SRR13764221_2.fastq.gz	Fastqsanger.gz
	SRR13764222_1.fastq.gz	Fastqsanger.gz

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Maternal DNA methylation regulates early trophoblast development

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DNA methylation in Vav-IDH1-KI mouse haematopoietic stem cells

Project description:Mutations in isocitrate dehydrogenase-1 (IDH1 R132) and -2 (IDH2 R140 and R172), which confer neomorphic enzymatic activity converting αKG (α-ketoglutarate) to D-2-hydroxyglutarate (D2HG), occur commonly in acute myeloid leukemia (AML). Mutant IDH1 alters epigenetics and increases haematopoietic progenitors in vivo, consistent with D2HG-mediated inhibition of TET2 5-methylcytosine hydroxylase. As TET2 mutations are mutually exclusive with IDH1/2 mutations and confer a similar phenotype, it has been widely believed that the oncogenicity of mutant IDH1/2 is due to TET2 inhibition. However, IDH1/2 mutations may have additional effects explaining the clinical features of MDS/MPN/AML. Here we show that mutant IDH1 downregulates ATM, thereby inhibiting DNA damage responses and increasing genomic instability. To investigate potential mechanisms of ATM downregulation, we examined ATM promoter DNA methylation in Vav-IDH1-KI long term haematopoietic stem cells (LT-HSC), short term haematopoietic stem cells (ST-HSC) and multipotent progenitors (MPP).

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DNA methylation regulates haematopoietic development

Project description:Focus on EHT and definitive hematopoiesis process including E10.0, E11.0, E14, Adult

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Hemi-methylated DNA regulates DNA methylation inheritance through allosteric control of H3 ubiquitylation by UHRF1

Project description:DNA methylation is a heritable chromatin modification essential to mammalian development that functions with histone post-translational modifications to regulate chromatin structure and gene expression programs. The epigenetic inheritance of DNA methylation requires the combined actions of DNMT1 and UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that facilitates DNMT1 recruitment to sites of newly replicated DNA through the ubiquitylation of histone H3. UHRF1 binds DNA with modest selectivity towards hemi-methylated CpG dinucleotides (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation inheritance but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. We further show that HeDNA functions as an allosteric regulator of UHRF1 ubiquitin ligase activity, directing ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies define a highly orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.

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