Higher Order Chromatin and Genetic Risk for Alzheimer's Disease

 描述(申请人提供)：阿尔茨海默氏症(AD)的遗传学研究进展迅速。在基因间、内含子和其他非编码序列中发现了越来越多的与风险相关的多态性和变异体。然而，设计可检验的假说来阐明这类与疾病相关的非编码DNA的潜在功能一直是一个重大挑战。这些序列中的许多被认为具有调节功能，包括与线性基因组上被许多千碱基散布的DNA隔开的转录起始点(TS)物理上相互作用的长程增强子元件。我们将首先生成组织和细胞群体(神经元、星形胶质细胞和小胶质细胞)中与AD病理生理相关的开放染色质和增强子序列的全面注释图。然后，我们将利用来自脑组织中两个大型、多区域RNAseq项目的高分辨率表达数量性状基因座(EQTL)图，并识别AD相关的非编码区，这些非编码区位于用组合组蛋白修饰签名标记的调节区内，组蛋白修饰签名指示活性增强子和TSS长距离相互作用的统计(EQTL)证据。然后，我们将使用神经表观遗传学中的创新方法，包括染色体构象捕捉(3C)来绘制人类死后脑组织中长程增强子-启动子相互作用的图谱。这里提出的多维方法提供了一个路线图，可以解开人类基因组中巨大但在很大程度上未被探索的非编码序列的神经功能。

 DESCRIPTION (provided by applicant): The genetics of Alzheimer's Dementia (AD) is advancing at rapid pace. An increasing number of risk- associated polymorphisms and variants are found in intergenic, intronic and other non-coding sequence. However, it has been a major challenge to design testable hypotheses to elucidate the potential function of such types of disease-associated non-coding DNA. Many of these sequences are thought to exert regulatory functions, including longe range enhancer elements physically interacting with transcription start sites (TSS) separated on the linear genome by many kilobases of interspersed DNA. We will first generate a comprehensive annotation map of open chromatin and enhancer sequences in tissue and cellular populations (neurons, astrocytes and microglia) that are relevant to the pathophysiology of AD. We will then leverage high resolution expression quantitative trait loci (eQTL) maps from two large, multiregional RNAseq projects in brain tissue and identify AD associated noncoding regions that are positioned within regulatory regions tagged with combinatorial histone modification signatures indicative of active enhancers and statistical (eQTL) evidence for long range TSS interactions. We then will employ innovative approaches in neuroepigenetics, including chromosome conformation capture (3C) to map long range enhancer-promoter interactions in human brain postmortem tissue. The multidimensional approach presented here provides a roadmap to unravel the neurological functions of the vast but in brain largely unexplored non-coding sequences of the human genome.