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Determination of a Novel Epigenetic Silencing Mechanism

新型表观遗传沉默机制的确定

基本信息

批准号：
9099408
负责人：
Ke Zhang Reid
金额：
$ 42.03万
依托单位：
WAKE FOREST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099408
关键词：
5&apos -exoribonuclease Affinity Chromatography Aging Binding Proteins Biological Assay Biology Cell physiology Cells Cellular biology Centromere Chemistry Chromatin Co-Immunoprecipitations Complex DNA Sequence Alteration Data Defect Development Doctor of Philosophy Endoribonucleases Environment Enzymes Epigenetic Process Etiology Eukaryota Exoribonucleases Fission Yeast Gene Expression Gene Expression Regulation Gene Silencing Genetic Genetic Transcription Genome Genomic approach Goals Growth and Development function Health Heterochromatin Human Link Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Methods Modeling Molecular Biology Organism Orthologous Gene Pathway interactions Phenotype Play Process Proteins Quality Control RNA RNA Interference RNA Interference Pathway RNA Processing Research Research Training Ribonucleases Ribosomal RNA Role Saccharomyces cerevisiae Saccharomycetales Small RNA Students Study models Syndrome Temperature Testing Transcript United States National Institutes of Health Universities Untranslated RNA Work base career chromatin immunoprecipitation college crosslink design epigenetic regulation epigenome exosome forest genetic analysis genetic information human disease innovation mutant novel poly A specific exoribonuclease programs protein protein interaction public health relevance transcription termination transcriptome undergraduate research

项目摘要

DESCRIPTION (provided by applicant): The Epigenome regulates when, where and how an organism uses the genetic information stored in its genome. It is essential to many cellular processes, such as the regulation of gene expression, genome organization and cell-fate determination. It also governs growth, development, and ultimately human health. Heterochromatin represents silenced chromatic domains, which are assembled and maintained through epigenetic mechanisms. Extensive studies have focused on the assembly of heterochromatin at centromeres mediated by the RNA interference (RNAi) pathway. Recent studies, including ours, indicate that the exosome, an RNA quality control and surveillance complex, performs in a parallel pathway with RNAi to mediate epigenetic silencing. Although both RNAi and the exosome pathways are RNA-mediated and involved in processing long noncoding RNAs (ncRNAs) into small RNAs, exactly how the exosome pathway participates in heterochromatin assembly is not been demonstrated. Whether other RNAi-independent RNA processing pathways participate in epigenetic silencing is also unknown. We have recently identified a RNA-processing mechanism in epigenetic silencing that works independently of both RNAi and the exosome. The proposed research aims are designed to test the hypothesis that Dhp1, a conserved 5' to 3' exoribonuclease and ortholog of budding yeast Rat1 and metazoan Xrn2, plays a heretofore unknown role in epigenetic silencing, beyond its established role in transcription termination. Genetic, cell biology, and genomic approaches will be employed to investigate: 1) the localization of Dhp1 at heterochromatic regions; 2) Dhp1 binding proteins; and 3) the enzymatic activity of Dhp1 and potential co-activators in epigenetic silencing. Results will clarify how various RNA-processing pathways, acting together or independently, contribute to epigenetic regulation of the eukaryotic genome, a fundamental mechanism of gene expression. This study will be carried out in fission yeast, Schizosaccharomyces pombe (S. pombe), a premier model for studying epigenetic silencing because of its conserved epigenetic components and suitability for powerful combinatory experimental methods as well as undergraduate research. This project is significant and innovative. It will define a novel RNA-processing mechanism in epigenetic silencing that works independently of both RNAi and the exosome. Additionally, it will be the first exploration into how Dhp1/Rat1/Xrn2 functions in chromatin-based silencing.

描述（由申请人提供）：表观基因组调节生物体何时、何地以及如何使用其基因组中存储的遗传信息。它对许多细胞过程至关重要，例如基因表达的调节，基因组组织和细胞命运决定。它还控制着生长、发育，最终控制着人类的健康。异染色质代表沉默的染色质结构域，其通过表观遗传机制组装和维持。大量的研究集中在由RNA干扰（RNAi）途径介导的异染色质在着丝粒的组装上。最近的研究，包括我们的研究，表明外泌体，RNA质量控制和监视复合物，在一个平行的途径与RNAi介导表观遗传沉默。虽然RNAi和外泌体途径都是RNA介导的，并参与将长非编码RNA（ncRNA）加工成小RNA，但外泌体途径如何参与异染色质组装尚未得到证实。其他RNAi非依赖性RNA加工途径是否参与表观遗传沉默也是未知的。我们最近已经确定了一种在表观遗传沉默中的RNA加工机制，该机制独立于RNAi和外泌体。所提出的研究目的旨在检验以下假设：Dhp1是一种保守的5 '至3'核糖核酸外切酶，是芽殖酵母Rat 1和后生动物Xrn 2的直系同源物，在表观遗传沉默中起着迄今为止未知的作用，超出了其在转录终止中的既定作用。将采用遗传学、细胞生物学和基因组学方法研究：1）Dhp1在异染色质区域的定位; 2）Dhp1结合蛋白; 3）Dhp1的酶活性和表观遗传沉默中的潜在共激活剂。结果将阐明各种RNA加工途径，共同或独立地发挥作用，有助于真核基因组的表观遗传调控，基因表达的基本机制。本研究将在裂殖酵母，裂殖酵母粟酒裂殖酵母（S。pombe），由于其保守的表观遗传组分和适用于强大的组合实验方法以及本科研究，是研究表观遗传沉默的首要模型。该项目具有重大意义和创新性。它将在表观遗传沉默中定义一种新的RNA加工机制，该机制独立于RNAi和外泌体。此外，这将是第一次探索Dhp1/Rat1/Xrn2如何在基于染色质的沉默中发挥作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Novel Epigenetic Silencing Pathway Involving the Highly Conserved 5'-3' Exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe.

DOI：
10.1371/journal.pgen.1005873
发表时间：
2016-02
期刊：
PLoS genetics
影响因子：
4.5
作者：
Tucker JF;Ohle C;Schermann G;Bendrin K;Zhang W;Fischer T;Zhang K
通讯作者：
Zhang K

The fission yeast MTREC and EJC orthologs ensure the maturation of meiotic transcripts during meiosis.

DOI：
10.1261/rna.055608.115
发表时间：
2016-09
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Marayati BF;Hoskins V;Boger RW;Tucker JF;Fishman ES;Bray AS;Zhang K
通讯作者：
Zhang K

Loss of Elongation-Like Factor 1 Spontaneously Induces Diverse, RNase H-Related Suppressor Mutations in Schizosaccharomyces pombe.

DOI：
10.1534/genetics.118.301055
发表时间：
2018-08
期刊：
Genetics
影响因子：
3.3
作者：
Marayati BF;Drayton AL;Tucker JF;Huckabee RH;Anderson AM;Pease JB;Zeyl CW;Zhang K
通讯作者：
Zhang K

A Deep-sequencing-assisted, Spontaneous Suppressor Screen in the Fission Yeast Schizosaccharomyces pombe.

裂殖酵母裂殖酵母中的深度测序辅助自发抑制子筛选。