title: Non-CpG methylation by DNMT3B facilitates REST binding and gene silencing in developing mouse hearts.
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-CpG methylation. 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 silencing mechanism in developing mammalian hearts that is regulated by the dynamic interaction of DNMT3B-mediated non-CpG methylation and REST binding.
authors.affiliation: Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Bingruo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Lu
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Tamilla
authors.initials: T
authors.lastname: Nechiporuk
authors.affiliation: German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.affiliation: Departments of Genetics, Medicine (Hematology), and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.affiliation: Departments of Genetics, Neurology, and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006321:Heart / Q000196:embryology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D000097584:DNA Methyltransferase 3B; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; D000099229:RE1-Silencing Transcription Factor; C578711:Hcn2 protein, mouse