Guo Junjie U, Szulwach Keith E, Su Yijing, Li Yujing, Yao Bing, Xu Zihui, Shin Joo Heon, Xie Bing, Gao Yuan, Ming Guo-Li, Jin Peng, Song Hongjun
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Front Biol (Beijing). 2014 Feb;9(1):66-74. doi: 10.1007/s11515-014-1295-1.
Mounting evidence points to critical roles for DNA modifications, including 5-methylcytosine (5mC) and its oxidized forms, in the development, plasticity and disorders of the mammalian nervous system. The novel DNA base 5-hydroxymethylcytosine (5hmC) is known to be capable of initiating passive or active DNA demethylation, but whether and how extensively 5hmC functions in shaping the post-mitotic neuronal DNA methylome is unclear. Here we report the genome-wide distribution of 5hmC in dentate granule neurons from adult mouse hippocampus . 5hmC in the neuronal genome is highly enriched in gene bodies, especially in exons, and correlates with gene expression. Direct genome-wide comparison of 5hmC distribution between embryonic stem cells and neurons reveals extensive differences, reflecting the functional disparity between these two cell types. Importantly, integrative analysis of 5hmC, overall DNA methylation and gene expression profiles of dentate granule neurons reveals the genome-wide antagonism between these two states of cytosine modifications, supporting a role for 5hmC in shaping the neuronal DNA methylome by promoting active DNA demethylation.
越来越多的证据表明，包括5-甲基胞嘧啶（5mC）及其氧化形式在内的DNA修饰在哺乳动物神经系统的发育、可塑性和疾病中起着关键作用。新发现的DNA碱基5-羟甲基胞嘧啶（5hmC）已知能够启动被动或主动DNA去甲基化，但5hmC在塑造有丝分裂后神经元DNA甲基化组中的作用以及作用程度尚不清楚。在此，我们报告了成年小鼠海马齿状颗粒神经元中5hmC的全基因组分布。神经元基因组中的5hmC在基因体中高度富集，尤其是在外显子中，并且与基因表达相关。对胚胎干细胞和神经元之间5hmC分布进行全基因组直接比较，发现了广泛差异，这反映了这两种细胞类型之间的功能差异。重要的是，对齿状颗粒神经元的5hmC、总体DNA甲基化和基因表达谱进行综合分析，揭示了这两种胞嘧啶修饰状态在全基因组范围内的拮抗作用，支持了5hmC通过促进主动DNA去甲基化在塑造神经元DNA甲基化组中发挥作用。
