美国北卡罗来纳大学教堂山分校Jason L. Stein研究组在研究中取得进展。他们发现在人类神经元分化过程中,遗传变异对染色质可及性的细胞类型特异性影响。相关论文于2021年5月20日发表于国际顶尖学术期刊《自然-神经科学》杂志上。
为了模拟人类皮层发育过程中常见遗传变异对非编码基因组的功能影响,他们使用测序(ATAC-seq)进行了转座酶可及染色质的测定,并分析了人类培养的神经祖细胞中的染色质可及性定量特征位点(QTL)。它们来自87个供体的分化神经元后代。他们确定了对988 / 1,839神经元/祖细胞调节元件的重大遗传效应,具有高度的细胞类型和时间特异性效应。染色质可及性-QTL的一个亚群(约30%)也与基因表达的变化有关。
转录激活子的基序破坏等位基因通常会导致染色质可及性降低,而抑制子的基序破坏等位基因会导致染色质可及性的提高。通过整合特定细胞类型的染色质可及性-QTL和与大脑相关的全基因组关联数据,他们能够精细定位和识别非编码性神经精神疾病风险基因座的调控机制。
据介绍,神经精神疾病的常见遗传风险富含皮质神经发生过程中活跃的调节因子。然而,关于这些变体如何影响基因调控仍然知之甚少。
附:英文原文
Title: Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation
Author: Dan Liang, Angela L. Elwell, Nil Aygn, Oleh Krupa, Justin M. Wolter, Felix A. Kyere, Michael J. Lafferty, Kerry E. Cheek, Kenan P. Courtney, Marianna Yusupova, Melanie E. Garrett, Allison Ashley-Koch, Gregory E. Crawford, Michael I. Love, Luis de la Torre-Ubieta, Daniel H. Geschwind, Jason L. Stein
Issue&Volume: 2021-05-20
Abstract: Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, it remains poorly understood as to how these variants influence gene regulation. To model the functional impact of common genetic variation on the noncoding genome during human cortical development, we performed the assay for transposase accessible chromatin using sequencing (ATAC-seq) and analyzed chromatin accessibility quantitative trait loci (QTL) in cultured human neural progenitor cells and their differentiated neuronal progeny from 87 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (roughly 30%) of chromatin accessibility-QTL were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type-specific chromatin accessibility-QTL and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying noncoding neuropsychiatric disorder risk loci.
DOI: 10.1038/s41593-021-00858-w
Source: https://www.nature.com/articles/s41593-021-00858-w
Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新IF:21.126
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex