Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons.
Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons.
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常见的精神分裂症风险变异体在人类海马神经元的开放染色质区域中富集。
DOI：
10.1038/s41467-020-19319-2
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发表时间：
2020-11-04
影响因子：
16.6
通讯作者：
Roussos P
中科院分区：
文献类型：
--
作者：
Hauberg ME;Creus-Muncunill J;Bendl J;Kozlenkov A;Zeng B;Corwin C;Chowdhury S;Kranz H;Hurd YL;Wegner M;Børglum AD;Dracheva S;Ehrlich ME;Fullard JF;Roussos P
人脑细胞的染色质景观包含了理解大脑功能的关键信息。在这里，我们使用ATAC-seq分析人类死后大脑样本中来自三个不同大脑区域（前扣带皮层，背外侧前额叶皮层和初级视觉皮层）的四种不同细胞群（海马神经元，GABA能神经元，少突胶质细胞和小胶质细胞/星形胶质细胞）的染色质结构。我们发现，染色质的可及性变化很大，细胞类型，更温和，由大脑区域，与mammatergic神经元显示最大的区域变异性。转录因子足迹涉及细胞特异性转录调控因子，并推断蛋白质编码基因、长基因间非编码RNA和microRNA的细胞特异性调控。体内转基因小鼠实验验证了这些人源调控序列中的几个的细胞类型特异性。我们发现，开放的染色质区域中的海马神经元丰富的神经精神疾病的风险变异，特别是那些与精神分裂症。将细胞特异性染色质数据与精神分裂症大脑的大量组织研究相结合，增加了统计功效，并证实了多巴胺能神经元受到的影响最大。这些发现说明了在人脑等复杂组织中研究细胞类型特异性表观基因组的实用性，以及这些方法更好地了解人脑功能遗传基础的潜力。在这里，作者对来自人类大脑三个不同区域的四种不同细胞群进行了ATAC-seq，发现染色质可及性因细胞类型而异，而因大脑区域而异。这项研究揭示了生物功能和基因调控的差异，以及与精神分裂症和其他神经精神特征相关的遗传变异的重叠。
The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function. Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.
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影响因子：
9.8
作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
46.9
作者：
Ernst J;Kellis M
通讯作者：
Kellis M
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
64.5
作者：
de la Torre-Ubieta L;Stein JL;Won H;Opland CK;Liang D;Lu D;Geschwind DH
通讯作者：
Geschwind DH