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Epigenetic regulation through the formation and resolution of R loops

通过 R 环的形成和解析进行表观遗传调控

基本信息

批准号：
9350668
负责人：
Kavitha Sarma
金额：
$ 285万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-08-31
项目状态：
已结题

项目摘要

Project Summary Chromatin, the packaging for DNA in the eukaryotic nucleus, is a dynamic entity that is affected by cellular processes such as replication, transcription and repair. Our views on gene regulation have evolved from simple notions about changes in DNA sequence, to a more complex perspective that takes into account multiple epigenetic factors such as chromatin structure, chromatin composition and three-dimensional genome organization. Over the last decade, much attention has been devoted to epigenetic alterations in chromatin, including post translational modifications of chromatin components, long non-coding RNAs that localize to and regulate genes, and most recently large scale changes in genome organization that affect interactions between distant genomic regions. However, one aspect of epigenetic gene regulation that has received a surprisingly small amount of attention is the changes in chromatin structure that occur as a consequence of transcription. Transcription is pervasive, with over 90% of the eukaryotic genome producing RNAs. The common chromatin structures that result from, and depend on transcription, such as R loops, are likely to contribute significantly to epigenetic gene regulation. But exactly how is not known. R loops are triplex nucleic acid structures formed during transcription when an RNA, either an mRNA or a long non-coding RNA, invades dsDNA, forming an RNA-DNA hybrid and a displaced ssDNA. Under normal conditions, R loops function in all aspects of gene regulation, but aberrant formation of R loops, or mutations in components that regulate them, is associated with several neurodegenerative diseases and cancers. R loops are especially relevant in repeat expansion disorders where their unscheduled formation results in aberrant transcription and disease pathology. But what causes R loops to form aberrantly or be resolved once created remains unknown. Identifying the molecular players that function at R loops is an important step toward targeting R loops for therapies for neurological disorders. We will develop new methodologies to isolate and identify R loop regulators, create a framework of molecular tools to elucidate mechanisms of these regulators and finally undertake a molecular screening approach to identify factors that facilitate transcription through a pathogenic R loop forming repeat. As a result, we expect to identify new regulators of R loops that can lead to novel therapeutic candidates for neurodegenerative repeat expansion disorders.

项目摘要染色质是真核细胞核中DNA的包装，是一个受影响的动态实体，通过细胞过程，如复制，转录和修复。我们对基因调控的看法已经从简单的DNA序列变化的概念发展到更复杂的考虑到多种表观遗传因素（例如染色质结构）的观点，染色质组成和三维基因组组织。在过去的十年里，注意力一直致力于染色质的表观遗传改变，包括翻译后染色质成分的修饰，定位于并调节基因，以及最近影响相互作用的基因组组织的大规模变化然而，表观遗传基因调控的一个方面，令人惊讶的是，作为转录的结果。转录是普遍的，超过90%的真核生物产生RNA的基因组。常见的染色质结构，转录，如R环，可能对表观遗传基因调控有显著贡献。但具体是如何做到的还不清楚。 R环是三链体核酸结构，当RNA（mRNA或长的非编码RNA）侵入dsDNA时，在正常情况下，R环在所有的细胞中都起作用。基因调控方面，但R环的异常形成，或调节它们，与几种神经退行性疾病和癌症有关。尤其与重复扩张性疾病相关，其中它们的非计划性形成导致异常转录和疾病病理。但是，是什么原因导致R环形成异常或一旦创建，则仍然未知。识别在R中起作用的分子参与者环是向靶向R环治疗神经系统疾病迈出的重要一步。我们将开发新的方法来隔离和识别R环调节器，创建一个框架，分子工具来阐明这些调节剂的机制，并最终进行分子通过致病性R环鉴定促进转录的因子的筛选方法因此，我们希望确定新的R环调节剂，可以导致新的用于神经变性重复扩增障碍的治疗候选物。