Non-CpG methylation by DNMT3B facilitates REST binding and gene silencing in developing mouse hearts

Donghong Zhang, Bingruo Wu, Ping Wang, Yidong Wang, Pengfei Lu, Tamilla Nechiporuk, Thomas Floss, John M. Greally, Deyou Zheng, Bin Zhou

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The dynamic interaction of DNA methylation and transcription factor binding in regulating spatiotemporal gene expression is essential for embryogenesis, but the underlying mechanisms remain understudied. In this study, using mouse models and integration of in vitro and in vivo genetic and epigenetic analyses, we show that the binding of REST (repressor element 1 (RE1) silencing transcription factor; also known as NRSF) to its cognate RE1 sequences is temporally regulated by non-CpGmethylation. This process is dependent on DNA methyltransferase 3B (DNMT3B) and leads to suppression of adult cardiac genes in developing hearts. We demonstrate that DNMT3B preferentially mediates non-CpG methylation of REST-targeted genes in the developing heart. Downregulation of DNMT3B results in decreased non-CpG methylation of RE1 sequences, reduced REST occupancy, and consequently release of the transcription suppression during later cardiac development. Together, these findings reveal a critical gene silencingmechanism in developing mammalian hearts that is regulated by the dynamic interaction of DNMT3B-mediated non-CpG methylation and REST binding.

Original languageEnglish (US)
Pages (from-to)3102-3115
Number of pages14
JournalNucleic Acids Research
Volume45
Issue number6
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Genetics

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