DNA methylation profile dynamics of tissue-dependent and differentially methylated regions during mouse brain development.
DNA methylation profile dynamics of tissue-dependent and differentially methylated regions during mouse brain development.
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DOI：
10.1186/1471-2164-14-82
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发表时间：
2013-02-06
期刊：
影响因子：
4.4
通讯作者：
Yagi S
中科院分区：
文献类型：
--
作者：
Hirabayashi K;Shiota K;Yagi S
组织及其组成细胞具有独特的DNA甲基化谱，包括组织依赖性和差异甲基化区域（T-DMRs）的DNA甲基化模式。先前的研究报道了DNA甲基化在细胞分化和发育中起着至关重要的作用。在这里，我们使用HpyCH4IV（一种甲基化敏感的限制性内切酶，可识别均匀分布在整个基因组中的ACGT残基）研究了来自不同发育阶段的小鼠神经祖细胞的全基因组DNA甲基化谱。利用基于微阵列的全基因组DNA甲基化分析系统，研究了转录起始位点（tss）周围8.5 kb区域，分析了胚胎期11.5 （E11.5NSph）和14.5 （E14.5NSph）和成年脑（AdBr）小鼠端脑神经球的DNA甲基化谱。我们发现在E11.5NSph和E14.5NSph之间，涉及神经发育和/或与人类神经疾病相关的基因（如Dclk1、Nrcam、Nfia和Ntng1）上的T-DMRs具有不同的DNA甲基化状态。这些T-DMRs不仅位于2 kb以内，而且距离tss远端（几个kbs）， E11.5NSph中低甲基化的T-DMRs往往位于CpG岛（CGI-）相关基因中。大多数在神经球中低甲基化的T-DMRs也在AdBr中低甲基化。有趣的是，在祖细胞中低甲基化的T-DMRs中，有一些在AdBr中高甲基化的T-DMRs。尽管包括Ntng1在内的某些基因在上游5 ‘处高度甲基化了T-DMRs，但我们在其tss下游3 ’处的AdBr处发现了低甲基化的T-DMRs。这一观察结果可以解释为什么ntn1在AdBr中高表达，尽管上游有高甲基化。小鼠成年脑DNA甲基化和基因表达谱可归因于神经相关基因中T-DMRs的发育动力学。
Tissues and their component cells have unique DNA methylation profiles comprising DNA methylation patterns of tissue-dependent and differentially methylated regions (T-DMRs). Previous studies reported that DNA methylation plays crucial roles in cell differentiation and development. Here, we investigated the genome-wide DNA methylation profiles of mouse neural progenitors derived from different developmental stages using HpyCH4IV, a methylation-sensitive restriction enzyme that recognizes ACGT residues, which are uniformly distributed across the genome. Using a microarray-based genome-wide DNA methylation analysis system focusing on 8.5-kb regions around transcription start sites (TSSs), we analyzed the DNA methylation profiles of mouse neurospheres derived from telencephalons at embryonic days 11.5 (E11.5NSph) and 14.5 (E14.5NSph) and the adult brain (AdBr). We identified T-DMRs with different DNA methylation statuses between E11.5NSph and E14.5NSph at genes involved in neural development and/or associated with neurological disorders in humans, such as Dclk1, Nrcam, Nfia, and Ntng1. These T-DMRs were located not only within 2 kb but also distal (several kbs) from the TSSs, and those hypomethylated in E11.5NSph tended to be in CpG island (CGI-) associated genes. Most T-DMRs that were hypomethylated in neurospheres were also hypomethylated in the AdBr. Interestingly, among the T-DMRs hypomethylated in the progenitors, there were T-DMRs that were hypermethylated in the AdBr. Although certain genes, including Ntng1, had hypermethylated T-DMRs 5′ upstream, we identified hypomethylated T-DMRs in the AdBr, 3′ downstream from their TSSs. This observation could explain why Ntng1 was highly expressed in the AdBr despite upstream hypermethylation. Mouse adult brain DNA methylation and gene expression profiles could be attributed to developmental dynamics of T-DMRs in neural-related genes.
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