Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Neurosci. 2019 Feb;22(2):307-316. doi: 10.1038/s41593-018-0297-8. Epub 2019 Jan 14.
Epigenetic modifications confer stable transcriptional patterns in the brain, and both normal and abnormal brain function involve specialized brain regions. We examined DNA methylation by whole-genome bisulfite sequencing in neuronal and non-neuronal populations from four brain regions (anterior cingulate gyrus, hippocampus, prefrontal cortex, and nucleus accumbens) as well as chromatin accessibility in the latter two. We find pronounced differences in both CpG and non-CpG methylation (CG-DMRs and CH-DMRs) only in neuronal cells across brain regions. Neuronal CH-DMRs were highly associated with differential gene expression, whereas CG-DMRs were consistent with chromatin accessibility and enriched for regulatory regions. These CG-DMRs comprise ~12 Mb of the genome that is highly enriched for genomic regions associated with heritability of neuropsychiatric traits including addictive behavior, schizophrenia, and neuroticism, thus suggesting a mechanistic link between pathology and differential neuron-specific epigenetic regulation in distinct brain regions.
表观遗传修饰赋予大脑稳定的转录模式，正常和异常的大脑功能都涉及特定的大脑区域。我们通过全基因组亚硫酸氢盐测序，研究了四个脑区（前扣带回皮层、海马体、前额叶皮层和伏隔核）的神经元和非神经元群体中的 DNA 甲基化，以及后两者的染色质可及性。我们发现，只有在神经元细胞中，跨脑区的 CpG 和非 CpG 甲基化（CG-DMR 和 CH-DMR）存在显著差异。神经元 CH-DMR 与差异基因表达高度相关，而 CG-DMR 与染色质可及性一致，并富含调控区域。这些 CG-DMR 约占基因组的 12Mb，高度富集与神经精神特征（包括成瘾行为、精神分裂症和神经质）的遗传率相关的基因组区域，这表明在不同的大脑区域中，病理与神经元特异性差异表观遗传调控之间存在机制联系。
