Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes.
DNA methylation at proximal promoters facilitates lineage restriction by silencing cell type-specific genes. However, euchromatic DNA methylation frequently occurs in regions outside promoters. The functions of such nonproximal promoter DNA methylation are unclear. Here we show that the de novo DNA methyltransferase Dnmt3a is expressed in postnatal neural stem cells (NSCs) and is required for neurogenesis. Genome-wide analysis of postnatal NSCs indicates that Dnmt3a occupies and methylates intergenic regions and gene bodies flanking proximal promoters of a large cohort of transcriptionally permissive genes, many of which encode regulators of neurogenesis. Surprisingly, Dnmt3a-dependent nonproximal promoter methylation promotes expression of these neurogenic genes by functionally antagonizing Polycomb repression. Thus, nonpromoter DNA methylation by Dnmt3a may be used for maintaining active chromatin states of genes critical for development.
Wu
Hao
H
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA. haowu7@gmail.com
Coskun
Volkan
V
Tao
Jifang
J
Xie
Wei
W
Ge
Weihong
W
Yoshikawa
Kazuaki
K
Li
En
E
Zhang
Yi
Y
Sun
Yi Eve
YE
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D021901:DNA, Intergenic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000254:growth & development; D055495:Neurogenesis / Q000235:genetics*; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D014158:Transcription, Genetic
D021901:DNA, Intergenic; C000715535:Dnmt3a protein, mouse; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A