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Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation

ABSTRACT: Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation

PROVIDER: PRJNA748062 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15193609.fastq.gz	Fastqsanger.gz
	SRR15193610.fastq.gz	Fastqsanger.gz
	SRR15193611.fastq.gz	Fastqsanger.gz
	SRR15193612.fastq.gz	Fastqsanger.gz
	SRR15193613.fastq.gz	Fastqsanger.gz

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Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [RNA-seq]

Project description:DNA methyltransferase 3A (DNMT3A) is the most frequently mutated gene in clonal hematopoiesis, indicating that it may be essential for hematopoietic differentiation. We therefore addressed the functional relevance of DNMT3A for hematopoietic differentiation of human induced pluripotent stem cells (iPSCs) by knocking out either exon 2, 19, or 23. Directed differentiation towards mesenchymal stromal cells or hematopoietic progenitor cells (iHPCs) was only slightly reduced in exon 19-/- lines. Notably, exon 19-/- and exon 23-/- lines revealed absence of almost the entire de novo DNA methylation during differentiation. Despite the drastic effects on DNA methylation, there was no significant impact on gene expression of iHPCs. Notably, DNA methylation differences in acute myeloid leukemia with/without DNMT3A are related to iHPCs with/without DNMT3A knockout. Our results demonstrate that de novo DNA methylation during hematopoietic differentiation of iPSCs is almost entirely dependent on DNMT3A, while it has little impact on early cell-fate decisions.

2022-05-31 | GSE180403 | GEO

Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [DNA methylation]

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Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [RNA-seq]

Project description:Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [RNA-seq]

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Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [DNA methylation]

Project description:Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [DNA methylation]

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Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation

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

2022-05-31 | GSE180404 | GEO

Structural basis for DNMT3A-mediated de novo DNA methylation

Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contact with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Hematological cancer-associated somatic mutations at the substrate-binding sites decrease DNMT3A activity, induce CpG hypomethylation and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its etiologic link to human disease.

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Structural basis for DNMT3A-mediated de novo DNA methylation (eRRBS)

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Genome-wide identification of distinct target loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Project description:DNA methylation plays essential roles in mammalian development. During post-implantation development, de novo establishment of DNA methylation is accomplished by DNA methyltransferases, in particular DNMT3A and DNMT3B. At present, the distinct functions of these two enzymes remain largely elusive. To comprehensively identify the target sites for de novo DNA methylation by the DNMT3 enzymes, we took advantage of female mouse ES cells established in the presence of MEK and Gsk3 inhibitors, which lack most DNA methylation (2i/L ES cells), in combination with genetic ablation of Dnmt3a or Dnmt3b. We analyzed de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from Dnmt3 knockout (KO) 2i/L ES cells. Both Dnmt3a and Dnmt3b KO 2i-MEFs exhibited a modest but global reduction in CpG methylation, which was particularly notable on the X chromosome in Dnmt3b KO cells. Although most genes were methylated similarly in both knockouts, we identified 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b KO 2i-MEFs, respectively. Notably, Dnmt3a was exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes. Consistent with this, tissue-specific DNA methylation at PcG target developmental genes was substantially reduced in Dnmt3a KO embryos. Finally, we found that human patients with DNMT3A mutant acute myeloid leukemia (AML) or harboring DNMT3B mutation associated with immunodeficiency, centromere, and facial anomalies (ICF) syndrome exhibited reduced CpG methylation at regions that were hypomethylated in Dnmt3a or Dnmt3b KO 2i-MEFs, respectively. Collectively, our findings in DNA-hypomethylated 2i/L ES cells revealed a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.

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