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"R-loop formation protects CpG islands against epigenetic silencing".

“R 环的形成可保护 CpG 岛免受表观遗传沉默”。

基本信息

批准号：
9116990
负责人：
Frederic Louis Chedin
金额：
$ 9.6万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116990
关键词：
Aberrant DNA Methylation Address Affect Algorithms Base Pairing Binding Biochemical Biological Assay Cell Culture System Cells Characteristics Complex CpG Islands DNA DNA Methylation DNA Modification Methylases DNA Sequence Elements Enzymes Epigenetic Process Evolution Exoribonuclease II Family Genes Genetic Transcription Genome Genomic approach Genomics Health High-Throughput Nucleotide Sequencing Histones Human Human Genome Immune System Diseases Immunity In Vitro Knowledge Lead Malignant Neoplasms Maps Measures Mediating Methods Methylation Molecular Conformation Molecular Genetics Mus Mutation Patients Pattern Process Property Proteins RNA Recruitment Activity Relative (related person)Reporting Single-Stranded DNA Site Structure Syndrome System Testing Tetanus Helper Peptide base chromatin immunoprecipitation embryonic stem cell genetic approach histone methyltransferase human disease imprint methylation pattern novel prevent promoter ribonuclease H1 ribonuclease HII scale up small hairpin RNA vertebrate genome

项目摘要

DESCRIPTION (provided by applicant): Project Summary: CpG islands (CGIs) function as promoters for greater than 60% of human genes. Importantly, these elements remain mostly free of CpG methylation - an epigenetic mark associated with stable transcriptional silencing - despite the fact that the vast majority of CpG sites in the genome are methylated. While the relative immunity of CGIs against epigenetic silencing has been noted for years and is critical to their function, its underlying mechanism has remained elusive. Here, we report three novel and key observations relevant to this process: (i) a large fraction of CGI promoters, while GC-rich overall, display marked strand asymmetry, or skew, in the distribution of G and C residues; (ii) transcription through such regions of high GC-skew leads to the formation of long R-loop structures in which the newly transcribed G-rich RNA remains hybridized to the template C-rich DNA strand, forcing the non-template DNA strand into a largely single-stranded conformation; and (iii) R-loop formation protects the underlying DNA sequence from the action of DNA methyltransferases (DNMTs). Based on this knowledge, we hypothesize that R-loop formation at mammalian CGI promoters serves to protect these regions against epigenetic silencing. We propose to further test this hypothesis through three Specific Aims combining computational, genomics, biochemical, and molecular genetics approaches in human and mouse cells. Specific Aim 1: To test the hypothesis that R-loop formation is a widespread and conserved property of mammalian CGI promoters. Specific Aim 2: To test the hypothesis that R-loop formation protects against DNA methylation. Specific Aim 3: To test the hypothesis that altered R-loop formation leads to aberrant DNA methylation patterns.

项目简介：CpG岛（cgi）是超过60%的人类基因的启动子。重要的是，尽管基因组中绝大多数CpG位点被甲基化，但这些元件大部分仍然没有CpG甲基化——一种与稳定转录沉默相关的表观遗传标记。虽然多年来人们已经注意到cgi对表观遗传沉默的相对免疫，并且对其功能至关重要，但其潜在机制仍然难以捉摸。在这里，我们报告了与这一过程相关的三个新颖和关键的观察结果：(i)大部分CGI启动子，虽然总体上富含gc，但在G和C残基的分布中显示出明显的链不对称或倾斜；（ii）通过这些高GC-skew区域的转录导致长r环结构的形成，其中新转录的富含g的RNA仍然与模板富含c的DNA链杂交，迫使非模板DNA链大部分变成单链构象；（iii） r环的形成保护底层DNA序列免受DNA甲基转移酶（dnmt）的作用。基于这些知识，我们假设哺乳动物CGI启动子上的r环形成有助于保护这些区域免受表观遗传沉默。我们建议通过结合计算、基因组学、生化和分子遗传学方法在人类和小鼠细胞中进一步验证这一假设。具体目的1：验证r环形成是哺乳动物CGI启动子广泛且保守的特性的假设。具体目标2：验证r环的形成可以防止DNA甲基化的假设。具体目标3：验证改变r环形成导致异常DNA甲基化模式的假设。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nascent Connections: R-Loops and Chromatin Patterning.

DOI：
10.1016/j.tig.2016.10.002
发表时间：
2016-12
期刊：
Trends in genetics : TIG
影响因子：
0
作者：
Chédin F
通讯作者：
Chédin F

Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.

DOI：
10.1038/ncomms14015
发表时间：
2017-01-24
期刊：
Nature communications
影响因子：
16.6
作者：
Sagie S;Toubiana S;Hartono SR;Katzir H;Tzur-Gilat A;Havazelet S;Francastel C;Velasco G;Chédin F;Selig S
通讯作者：
Selig S

GC skew is a conserved property of unmethylated CpG island promoters across vertebrates.