Dnmt3a Promotes Transcription by Antagonizing Polycomb Repression in Neural Stem Cells
Hao Wu1, Volkan Coskun1, Wei Xie2, Jifang Tao1, En Li3, Kazuaki Yoshikawa4, Yi Zhang5, Yi Eve Sun1,*
De novo DNA methyltransferases epigenetically modify the genome by cytosine methylation and are essential for mammalian development. However, the identities of genes targeted by de novo DNA methyltransferases and how these enzymes regulate their target genes during development remain obscure. Here, genome-wide analysis of the de novo DNA methyltransferase Dnmt3a in multipotent neural stem/progenitor cells （NPCs） shows that Dnmt3a occupies and methylates genomic regions flanking proximal promoters of transcriptionally permissive genes, many of which are key regulators of neural development. We demonstrate that Dnmt3a antagonizes binding of Polycomb repression complex 2 （PRC2） to chromatin in a methyltransferase activity-dependent manner, thereby opposing PRC2-mediated repressive histone modification to promote expression of genes required for neurogenesis. Importantly, Dnmt3a-deficiency impairs neurogenesis from NPCs in culture and in postnatal mouse forebrains. Together, our studies reveal that de novo DNA methyltransferases can facilitate transcriptional activation of differentiation programs in tissue-specific stem cells by antagonizing Polycomb repression.
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