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.

项目概要染色质是真核细胞核中 DNA 的包装，是一个受到影响的动态实体我们对基因调控的看法。已经从关于 DNA 序列变化的简单概念演变为更复杂的概念考虑到染色质结构等多种表观遗传因素的观点，染色质组成和三维基因组组织。人们的注意力集中在染色质的表观遗传改变上，包括翻译后染色质成分的修饰，长链非编码 RNA 定位并调节基因，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是在遥远的基因组区域之间。令人惊讶的是，染色质结构发生的变化受到的关注很少作为转录的结果。转录是普遍存在的，超过 90% 的真核生物产生 RNA 的常见染色质结构。转录，例如 R 环，可能对表观遗传基因调控做出重大贡献。但R环究竟是如何形成的尚不清楚。当 RNA（mRNA 或长非编码 RNA）侵入 dsDNA 时进行转录，形成 RNA-DNA 杂交体和置换的 ssDNA 在正常情况下，R 环在所有细胞中都起作用。基因调控方面的问题，但 R 环的异常形成或组件的突变 R 环与多种神经退行性疾病和癌症有关。特别与重复扩张障碍相关，其中它们的非计划形成导致转录异常和疾病病理学是什么导致 R 环异常形成？一旦创建就解决了仍然未知。循环是针对 R 循环治疗神经系统疾病的重要一步。将开发新方法来隔离和识别 R 环路调节器，创建一个框架分子工具来阐明这些调节剂的机制，并最终进行分子研究筛选方法来识别通过致病性 R 环促进转录的因子因此，我们期望找到新的 R 环调节因子，从而产生新颖的结果。神经退行性重复扩张障碍的治疗候选者。