An atlas of chromatin accessibility in the adult human brain.
An atlas of chromatin accessibility in the adult human brain.
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DOI：
10.1101/gr.232488.117
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发表时间：
2018-08
期刊：
影响因子：
7
通讯作者：
Roussos P
中科院分区：
文献类型：
--
作者：
Fullard JF;Hauberg ME;Bendl J;Egervari G;Cirnaru MD;Reach SM;Motl J;Ehrlich ME;Hurd YL;Roussos P
与神经精神疾病相关的大多数常见遗传风险变异是非编码的，并且被认为通过破坏顺式调节元件（cre）的功能来发挥其作用，包括启动子和增强子。在每个细胞内，染色质以特定的模式排列，以暴露基因表达的最佳时空调节所需的cre库。为了进一步了解大脑中调节转录的复杂机制，我们使用冷冻的尸体样本来生成迄今为止最大的人类大脑和细胞类型特异性开放染色质数据集。利用转座酶可及染色质分析和测序（ATAC-seq），我们在5个个体的14个不同的大脑区域中创建了两种细胞类型（神经元和非神经元）的染色质可及性图谱。染色质结构因细胞类型而异，神经元染色质比非神经元染色质表现出更高的区域变异性。我们的发现之一是纹状体神经元的开放染色质区域（OCR）。当置于小鼠体内时，由该OCR衍生的人类序列概括了ATAC-seq实验预测的细胞类型和区域表达模式。此外，不同可及的染色质与神经精神特征的遗传结构重叠，并确定分子途径和生物学功能的差异。通过转录因子结合分析，我们鉴定出具有细胞类型和脑区域特异性的蛋白质编码rna和长链非编码rna （lncRNAs）。我们的数据为研究界提供了宝贵的资源，我们将这个人脑染色质可及性图谱作为一个在线数据库“brain Open chromatin atlas （BOCA）”提供，以方便解释。
Most common genetic risk variants associated with neuropsychiatric disease are noncoding 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 understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type–specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five 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 provide 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.
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