美国北岸大学Jubao Duan和芝加哥大学Xin He研究团队，合作利用人诱导多能干细胞（iPSC）神经元中的等位基因特异性开放染色质阐明了功能性疾病变体。相关论文于2020年7月31日发表于《科学》杂志。

由于调节序列通常位于开放染色质中，因此研究人员认为神经精神疾病风险变异可能会影响神经发育过程中染色质的可及性。使用人诱导多能干细胞（iPSC）衍生的神经元来模拟大脑发育，研究人员鉴定了成千上万个具有等位基因特异性的开放染色质（ASoC）遗传变异。这些神经元ASoC部分受转录因子结合改变的诱导，在脑基因增强子和表达定量性状基因座中过分表达，并经常通过染色质接触与远端基因相关联。

ASoC丰富了与脑部疾病相关的遗传变异，从而能够鉴定功能性精神分裂症的风险变异及其顺式调控的靶基因。这项研究揭示了ASoC作为非编码神经精神病风险变异的功能机制，为识别疾病的因果变异和基因提供了强大的支持。

据悉，大多数精神疾病的风险变异存在于非编码序列中，但缺乏对其功能的理解。

附：英文原文

Title: Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants

Author: Siwei Zhang, Hanwen Zhang, Yifan Zhou, Min Qiao, Siming Zhao, Alena Kozlova, Jianxin Shi, Alan R. Sanders, Gao Wang, Kaixuan Luo, Subhajit Sengupta, Siobhan West, Sheng Qian, Michael Streit, Dimitrios Avramopoulos, Chad A. Cowan, Mengjie Chen, Zhiping P. Pang, Pablo V. Gejman, Xin He, Jubao Duan

Issue&Volume: 2020/07/31

Abstract: Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)–derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.

DOI: 10.1126/science.aay3983

Source: https://science.sciencemag.org/content/369/6503/561