Brain function depends on interaction of diverse cell types whose gene expression and identity are defined, in part, by epigenetic mechanisms. Neuronal DNA contains two major epigenetic modifications, methylcytosine (mC) and hydroxymethylcytosine (hmC), yet their cell type-specific landscapes and relationship with gene expression are poorly understood. We report high-resolution (h)mC analyses, together with transcriptome and histone modification profiling, in three major cell types in human prefrontal cortex: glutamatergic excitatory neurons, medial ganglionic eminence-derived γ-aminobutyric acid (GABA)ergic inhibitory neurons, and oligodendrocytes. We detected a unique association between hmC and gene expression in inhibitory neurons that differed significantly from the pattern in excitatory neurons and oligodendrocytes. We also found that risk loci associated with neuropsychiatric diseases were enriched near regions of reduced hmC in excitatory neurons and reduced mC in inhibitory neurons. Our findings indicate differential roles for mC and hmC in regulation of gene expression in different brain cell types, with implications for the etiology of human brain diseases.

中文翻译：

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DNA（羟）甲基化在人类抑制性神经元表观遗传调控中的独特作用。

大脑功能取决于不同细胞类型的相互作用，这些细胞类型的基因表达和身份部分由表观遗传机制定义。神经元 DNA 包含两种主要的表观遗传修饰，甲基胞嘧啶 (mC) 和羟甲基胞嘧啶 (hmC)，但它们的细胞类型特异性景观以及与基因表达的关系知之甚少。我们报告了人类前额皮质三种主要细胞类型的高分辨率 (h)mC 分析以及转录组和组蛋白修饰分析：谷氨酸能兴奋性神经元、内侧神经节隆起衍生的 γ-氨基丁酸 (GABA) 能抑制性神经元和少突胶质细胞。我们在抑制性神经元中检测到 hmC 与基因表达之间存在独特的关联，该关联与兴奋性神经元和少突胶质细胞中的模式显着不同。我们还发现，与神经精神疾病相关的风险位点在兴奋性神经元中 hmC 减少和抑制性神经元中 mC 减少的区域附近富集。我们的研究结果表明，mC 和 hmC 在不同脑细胞类型的基因表达调节中发挥着不同的作用，这对人类大脑疾病的病因学具有重要意义。