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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.

项目总结