美国加州大学圣迭戈分校Christopher K. Glass课题组近日揭示，脑细胞类型特异性增强子与启动子相互作用图谱与疾病风险的关系。相关论文2019年11月14日在线发表于国际学术期刊《科学》。

为了更好地了解与脑疾病相关的常见遗传变异，研究人员为人脑的主要细胞类型定义了非编码调控区。精神疾病主要与转录增强子和神经元启动子的变异有关，而散发性的阿尔茨海默氏病（AD）变异则主要限于小胶质细胞增强子。将细胞类型特异性增强子中的疾病风险变异体与启动子关联的相互作用图谱揭示了AD中扩展的小胶质细胞基因网络。删除具有AD风险变体的小胶质细胞特异性增强子，可消除小胶质细胞中BIN1基因的表达，但不会破坏神经元或星形胶质细胞中的BIN1表达。这些发现修改并扩展了可能受AD非编码变异影响的基因，并暗示了它们可能在其中起作用的细胞类型。

据了解，非编码遗传变异是表型多样性的主要驱动因素，但其功能解释具有挑战性。

附：英文原文

Title: Brain cell type–specific enhancer-promoter interactome maps and disease risk association

Author: Alexi Nott, Inge R. Holtman, Nicole G. Coufal, Johannes C.M. Schlachetzki, Miao Yu, Rong Hu, Claudia Z. Han, Monique Pena, Jiayang Xiao, Yin Wu, Zahara Keulen, Martina P. Pasillas, Carolyn O’Connor, Christian K. Nickl, Simon T. Schafer, Zeyang Shen, Robert A. Rissman, James B. Brewer, David Gosselin, David D. Gonda, Michael L. Levy, Michael G. Rosenfeld, Graham McVicker, Fred H. Gage, Bing Ren, Christopher K. Glass

Issue&Volume: 2019/11/14

Abstract: AbstractNon-coding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined non-coding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable cell types in which they function.

DOI: 10.1126/science.aay0793

Source: https://science.sciencemag.org/content/early/2019/11/13/science.aay0793