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Nucleic Acids Res. 2019 Jun 20. pii: gkz520. doi: 10.1093/nar/gkz520. [Epub ahead of print]

DNMT3B shapes the mCA landscape and regulates mCG for promoter bivalency in human embryonic stem cells.

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Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599.
National University of Singapore Graduate School for Integrative Sciences and Engineering, 21 Lower Kent Ridge, Singapore 119077.
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.
Department of Translational Medicine, University of Eastern Piedmont, Novara, NO 28100, Italy.
Harvard Stem Cell Institute, Boston, MA 02115, USA.


DNMT3B is known as a de novo DNA methyltransferase. However, its preferential target sites for DNA methylation are largely unknown. Our analysis on ChIP-seq experiment in human embryonic stem cells (hESC) revealed that DNMT3B, mCA and H3K36me3 share the same genomic distribution profile. Deletion of DNMT3B or its histone-interacting domain (PWWP) demolished mCA in hESCs, suggesting that PWWP domain of DNMT3B directs the formation of mCA landscape. In contrast to the common presumption that PWWP guides DNMT3B-mediated mCG deposition, we found that deleting PWWP does not affect the mCG landscape. Nonetheless, DNMT3B knockout led to the formation of 2985 de novo hypomethylated regions at annotated promoter sites. Upon knockout, most of these promoters gain the bivalent marks, H3K4me3 and H3K27me3. We call them spurious bivalent promoters. Gene ontology analysis associated spurious bivalent promoters with development and cell differentiation. Overall, we found the importance of DNMT3B for shaping the mCA landscape and for maintaining the fidelity of the bivalent promoters in hESCs.


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