An Atlas of Chromatin Accessibility in the Adult Human Brain. Homo sapiens

The majority of common genetic risk variants associated with neuropsychiatric disease are non-coding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further our understanding of the complex mechanisms that modulate transcription in the brain, we utilized frozen postmortem samples to generate the largest human brain and cell type-specific open chromatin dataset to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in 2 cell types (neurons and non-neurons) across 14 distinct brain regions of 5 individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell-type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provides a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database “Brain Open Chromatin Atlas (BOCA)” to facilitate interpretation. Overall design: Open chromatin profiles in neuronal and non-neuronal nuclei from 14 brain regions of 5 control samples

绝大多数与神经精神疾病相关的常见遗传风险变异为非编码变异，被认为通过破坏顺式调控元件（cis regulatory elements, CRE）的功能发挥作用，包括启动子与增强子。在每个细胞中，染色质以特定模式排布，以暴露基因表达最佳时空调控所需的全套顺式调控元件。为加深我们对大脑中转录调控复杂机制的理解，本研究利用冰冻死后组织样本，构建了迄今为止规模最大的人类大脑细胞类型特异性开放染色质数据集。本研究采用转座酶可及性测序（Assay for Transposase Accessible Chromatin followed by sequencing, ATAC-seq）技术，绘制了5名个体14个不同脑区域内2种细胞类型（神经元与非神经元）的染色质可及性图谱。染色质结构随细胞类型存在显著差异，神经元染色质的区域变异程度高于非神经元染色质。本研究发现一个纹状体神经元特异性的开放染色质区域（open chromatin region, OCR）；将该区域来源的人类序列植入小鼠体内后，其可重现我们通过ATAC-seq实验预测的细胞类型特异性与区域特异性表达模式。此外，差异可及性染色质区域与神经精神疾病性状的遗传结构存在重叠，并可揭示分子通路与生物学功能的差异。通过转录因子结合分析，本研究鉴定出了具有细胞类型与脑区特异性的蛋白编码RNA及长链非编码RNA（long noncoding RNAs, lncRNAs）。本研究数据为科研社区提供了宝贵的研究资源，我们同时将该人类大脑染色质可及性图谱以在线数据库“大脑开放染色质图谱（Brain Open Chromatin Atlas, BOCA）”的形式对外发布，以方便相关研究解读。实验整体设计：对5名对照个体的14个脑区域内的神经元与非神经元细胞核进行开放染色质谱分析。