Schneider Eberhard, Dittrich Marcus, Böck Julia, Nanda Indrajit, Müller Tobias, Seidmann Larissa, Tralau Tim, Galetzka Danuta, El Hajj Nady, Haaf Thomas
Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Bioinformatics, Julius Maximilians University, 97074 Würzburg, Germany.
Gene. 2016 Oct 30;592(1):110-118. doi: 10.1016/j.gene.2016.07.058. Epub 2016 Jul 25.
Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.
正常人类大脑发育依赖于高度动态的表观遗传过程来进行时空基因调控。最近的研究发现胎儿大脑发育过程中DNA甲基化存在广泛变化。我们使用Illumina 450K甲基化芯片对27例孕12 - 42周胎儿额叶皮质中的CpG甲基化进行了分析。将与孕周呈现全基因组显著相关性的位点与一个来自孕3 - 26周的公开数据集进行比较。我们总共鉴定出2016个匹配的发育调控差异甲基化位点（m - dDMPs）：1767个m - dDMPs在胎儿发育过程中发生高甲基化，1149个发生低甲基化。m - dDMPs在CpG岛和基因启动子中所占比例较低，在基因体中富集。它们似乎聚集在某些染色体区域。m - dDMPs在自闭症相关基因和CpG中显著富集。我们的研究结果支持这样一种观点，即胎儿大脑发育过程中甲基化动态的降低可能易患自闭症。此外，m - dDMPs在具有人类特异性大脑表达模式和/或组蛋白修饰的基因中富集。总体而言，我们定义了一组在妊娠早期到晚期呈现持续甲基化变化的dDMPs。涉及顺式调控区域甲基化变化的相同表观遗传机制可能已被用于人类大脑的进化和个体发育。
