5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging

• Type of Material: Article
• Authors: Keith E. Szulwach, Emory University; Xuekun Li, Emory University; Yujing Li, Emory University; Chun-Xiao Song, The University of Chicago; Hao Wu, Emory University; Qing Dai, The University of Chicago; Hasan Irier, Emory University; Anup K Upadhyay, Emory University; Marla Gearing, Emory University; Allan I Levey, Emory University; Aparna Vasanthakumar, The University of Chicago; Lucy A Godley, The University of Chicago; Qiang Chang, University of Wisconsin-Madison; Xiaodong Cheng, Emory University; Chuan He, The University of Chicago; Peng Jin, Emory University
• Language: English
• Date: 2011-10-30
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011, Springer Nature
• Final Published Version (URL): http://www.nature.com/neuro/journal/v14/n12/full/nn.2959.html
• Title of Journal or Parent Work: Nature Neuroscience
• ISSN: 1097-6256
• Volume: 14
• Issue: 12
• Start Page: 1607
• End Page: 1616
• Grant/Funding Information: X.C. was supported by NIH grant GM049245 and is a Georgia Research Alliance Eminent Scholar. M.G. and A.I.L. are partially supported by Emory Alzheimer’s Disease Center (P50AG025688).; P.J. is supported by NIH grants (NS051630, MH076090 and P50AG025688) and Simons Foundation Autism Research Initiative.; L.A.G. is supported by NIH grants CA129831 and CA129831-03S1. C.H. was partially supported by NIH grant GM071440.; H.I. is supported by the Training Program in Human Disease Genetics funded by the US National Institutes of Health (NIH, T32MH087977).; This work was supported, in part, by the Emory Genetics Discovery Fund.
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pathology; Biology, Neuroscience

Abstract

DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base that is derived from 5-methylcytosine, accounts for ~40% of modified cytosine in the brain and has been implicated in DNA methylation–related plasticity. We mapped 5-hmC genome-wide in mouse hippocampus and cerebellum at three different ages, which allowed us to assess its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We found developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC–regulated regions revealed stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum, we found conserved genomic features of 5-hmC. Finally, we found that 5-hmC levels were inversely correlated with methyl-CpG–binding protein 2 dosage, a protein encoded by a gene in which mutations cause Rett syndrome. These data suggest that 5-hmC–mediated epigenetic modification is critical in neurodevelopment and diseases.