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DNMT3B maintains mCA landscape and regulates mCG status of bivalent promoters in human embryonic stem cells

ABSTRACT: In mammalian cells, DNMT3B is known as a de novo DNA methyltransferase. However, its preferential target sites for DNA methylation are largely unknown. By studying CA methylation (mCA) and various histone mark distributions in human embryonic stem cells (hESC), we set up a connection between mCA, H3K36me3, and DNMT3B. We found that mCA, H3K36me3 and DNMT3B signals in hESC are distributed in a 3-level pattern: low level at promoter region, intermediate level before first splicing junction and high level afterward. Knocking out DNMT3B (KO) in hESC demolished mCA, and this further confirmed that DNMT3B is the main enzyme which maintains mCA. Furthermore, the mCA could not be maintained after we deleted the H3K36me3 binding domain, PWWP domain, in DNMT3B. This observation suggests that DNMT3B maintains mCA through its histone interaction. This is the first study that describes the detailed landscape of mCA and its connection with DNMT3B. In contrast to mCA, we only observed a minor reduction of global mCG level from 83.7% to 79.2% after DNMT3B KO. 5256 de novo hypomethylated regions (dnHMRs) were found in the KO cell, in which 57.8% overlapped annotated promoter sites. Intriguingly, most of these promoter dnHMRs were bivalent, possessing both H3K4me3 and H3K27me3. We call them spurious bivalent promoters. Gene ontology (GO) analysis associated spurious bivalent promoters with development and cell differentiation. Overall, we found the importance of DNMT3B for shaping mCA landscape and maintaining the fidelity of bivalent promoter landscape in hESC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113881 | GEO | 2019/06/02

REPOSITORIES: GEO

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DNMT3B maintains mCA landscape and regulates mCG status of bivalent promoters in human embryonic stem cells

Project description:DNMT3B maintains mCA landscape and regulates mCG status of bivalent promoters in human embryonic stem cells

| PRJNA454322 | ENA

Unique cell cycle-dependent variations in the pluripotent epigenetic landscape define novel cohorts of temporal expressed bivalent genes during hESCs differentiation

Project description:By mapping the genomic enrichmentsÂ of H3K4me3 and H3K27me3 modifications in pure populations of hESCs during the G2, mitotic and G1 phases of the cell cycle, we characterize cell cycle-dependent variations in the epigenetic landscape of bivalent genes, altering the current view of mitotic inheritance in pluripotent cells. We identified novel classes of bivalent domains that are highly enriched with H3K4me3 during mitosis, depleted during G1 only, and ubiquitously bivalent. These bivalent domains are associated with specific genes and expression patterns during differentiation. These cell cycle-dependent epigenetic profiles are unique to hESCs and are not observed following initiation of phenotype commitment. Our results establish a new dimension in cell cycle-dependent chromatin regulation that advances understanding of contributions the pluripotent epigenetic landscape to hESC identity. Study of two histone modifications, H3K4me3 and H3K27me3, during three cell cycle phases in two cell types. Study of gene expression from these two cell types in asynchronous cells.

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Unique cell cycle-dependent variations in the pluripotent epigenetic landscape define novel cohorts of temporal expressed bivalent genes during hESCs differentiation

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