Prediction and Validation of Oligodendrocyte Gene Regulatory Network from Multi-Omics

项目摘要 对几种智力/发育障碍(IDD)疾病的研究表明，白人 在其发病机制中的物质变化，以及少突胶质细胞缺陷的小鼠模型 证实了与认知障碍的机械性联系。此外，许多遗传原因导致 脑白质营养不良已被发现，包括影响PLP1基因的突变 Pelizaeus-Merzbacher病。然而，由于缺乏工具来解释意义重大的 非编码基因组中的变异，大多数遗传变异的最终影响 不幸的是，它仍然没有特征。有了SouEncode和GTEx的资源，一些 已经出现了许多工具，这些工具可以被集成来创建转录因子的网络模型 (TFS)及其结合位点(TFBS)，以及少突胶质细胞的几个相关数据集 表观基因组已经出现。这项提议的目标是整合这些表观基因组资源 利用新可用的eQTL资源开发一个模型，该模型将提高 破译各种疾病患者的全基因组测序(WGS)数据 与脑白质改变相关的发育障碍。在创建模型的同时，我们 将整合参与少突胶质细胞发育的已知转录因子(MYRF， SOX10、OLIG2、TCF4和CHD7/8)以确定变异体是否改变转录因子结合 少突胶质细胞表达基因的位点(TFBS)。我们预计这一创造将得到改进 少突胶质细胞GRN将导致在几种IDD情况下的协作性赠款合作， 如自闭症谱系障碍(ASD)，以阐明非编码变化对 WGS，并将它们与少突胶质细胞网络中的扰动联系起来。

PROJECT ABSTRACT Studies of several Intellectual/Developmental Disability (IDD) conditions have implicated white matter alterations in their pathogenesis, and mouse models of oligodendrocyte defects have validated mechanistic connections with cognitive disorders. In addition, many genetic causes of leukodystrophies have been identified, including mutations affecting the PLP1 gene in Pelizaeus-Merzbacher disease. However, due to the lack of tools to interpret significant variations in the noncoding genome, the ultimate influence of most genetic variants unfortunately remain uncharacterized. With the resources of PsychEncode and GTEx, a number of tools have emerged that can be integrated to create a network model of Transcription Factors (TFs) and their binding sites (TFBS), and several relevant datasets of the oligodendrocyte epigenome have emerged. The goal of this proposal is to integrate these epigenomic resources with newly available eQTL resources to develop a model that will improved predictive value in deciphering Whole Genome Sequencing (WGS) data from patients with a variety of developmental disabilities related to white matter changes. Along with creating the model, we will integrate motif analysis of known TFs involved in oligodendrocyte development (MYRF, SOX10, OLIG2, TCF4 and CHD7/8) to determine if variants alter transcription factor binding sites (TFBS) in oligodendrocyte-expressed genes. We anticipate that creation an improved oligodendrocyte GRN will lead to collaborative grant collaborations in several IDD conditions, such as Autism Spectrum Disorder (ASD), to elucidate the effects of noncoding changes in WGS and link them to perturbations in the oligodendrocyte network.