人类大脑皮质神经发生过程中开放染色质的动态景观。
The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis.
机构信息
Neurogenetics Program, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Neurogenetics Program, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
出版信息
Cell. 2018 Jan 11;172(1-2):289-304.e18. doi: 10.1016/j.cell.2017.12.014. Epub 2018 Jan 4.
Non-coding regions comprise most of the human genome and harbor a significant fraction of risk alleles for neuropsychiatric diseases, yet their functions remain poorly defined. We created a high-resolution map of non-coding elements involved in human cortical neurogenesis by contrasting chromatin accessibility and gene expression in the germinal zone and cortical plate of the developing cerebral cortex. We link distal regulatory elements (DREs) to their cognate gene(s) together with chromatin interaction data and show that target genes of human-gained enhancers (HGEs) regulate cortical neurogenesis and are enriched in outer radial glia, a cell type linked to human cortical evolution. We experimentally validate the regulatory effects of predicted enhancers for FGFR2 and EOMES. We observe that common genetic variants associated with educational attainment, risk for neuropsychiatric disease, and intracranial volume are enriched within regulatory elements involved in cortical neurogenesis, demonstrating the importance of this early developmental process for adult human cognitive function.
非编码区占人类基因组的大部分，并且包含神经精神疾病风险等位基因的很大一部分，但其功能仍未得到很好的定义。我们通过对比发育中的大脑皮层生发区和皮质板中的染色质可及性和基因表达，创建了一个涉及人类皮质神经发生的高分辨率非编码元件图谱。我们将远端调控元件（DRE）与其同源基因（连同染色质相互作用数据）联系起来，并表明人类获得性增强子（HGE）的靶基因调节皮质神经发生，并在外放射状胶质中富集，这是一种与人类皮质进化相关的细胞类型。我们通过实验验证了预测的 FGFR2 和 EOMES 增强子的调控作用。我们观察到与教育程度、神经精神疾病风险和颅内体积相关的常见遗传变异在参与皮质神经发生的调控元件中富集，这表明这个早期发育过程对成人的认知功能很重要。
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