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RNAi-Mediated Heterochromatin Assembly

RNAi介导的异染色质组装

基本信息

批准号：
8225222
负责人：
DANESH MOAZED
金额：
$ 34.74万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225222
关键词：
Address Base Pairing Biochemical Bypass Cell Nucleus Cells Chromatin Chromosomes Cleaved cell Complex DNA Sequence Dissection Double-Stranded RNA Enzymes Fission Yeast Functional RNA Gene Silencing Generations Genetic Transcription Goals Health Heterochromatin Histone H3 Histones Human In Vitro Intervention Knowledge Laboratories Link Lysine Mediating Methods Methylation Methyltransferase Molecular Molecular Chaperones Nucleic Acids Pathway interactions Play Process Proteins RNA RNA Binding RNA Interference RNA Interference Pathway RNA Precursors RNA Processing RNA Sequences RNA Splicing RNA chemical synthesis RNA-Directed RNA Polymerase Recruitment Activity Regulation Role Site Small Interfering RNA Testing Therapeutic Transcript Transgenes Viral Work base cancer cell differentiation design histone methyltransferase human DICER1 protein in vivo mutant novel preference programs protein protein interaction reconstitution transcription termination

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this work is to understand how the RNA interference (RNAi) pathway regulates heterochromatic gene silencing in fission yeast. RNAi is a widespread silencing mechanism that acts at both the posttranscriptional and transcriptional levels and is triggered by double stranded RNA molecules that are processed to small interfering RNAs (called siRNAs). siRNAs guide the inactivation of complementary target nucleic acids by effector complexes. Our laboratory has purified the RITS (RNA-Induced Transcriptional Gene Silencing) complex, containing the Ago1, Chp1, and Tas3 proteins, which physically links the RNAi pathway to heterochromatin. In addition, we have purified the RNAi complexes that synthesize dsRNA, process it into siRNAs, and help load siRNAs onto the RITS complex. We have provided evidence that these RNAi complexes localize to specific chromosome regions via base pairing interactions between siRNAs and nascent non-coding transcripts. This localization leads to recruitment of a histone H3 methyltransferase complex, called the CRC (Clr4-Rik1-Cul4) complex, which methylates histone H3 on lysine-9 and promotes heterochromatin formation. Our recent results suggest that cis-synthesis of dsRNA, at sites of heterochromatin assembly, is required for H3 lysine-9 methylation. The goals of this proposal are to understand how RITS and dsRNA synthesis recruit the CRC histone methyltransferase complex and how the nascent RNA transcript controls the spreading of heterochromatin. In addition, we will perform a biochemical dissection of steps that are involved in the formation of heterochromatic siRNAs. PUBLIC HEALTH RELEVANCE: This project addresses the role of RNA interference (RNAi), a conserved RNA silencing pathway, in gene silencing in the nucleus. Components of this pathway are involved in regulation of cell differentiation and cancer in humans. A basic understanding of the role of RNAi in gene silencing will not only provide a frame work for understanding how the process can fail, but also provides the substrate and knowledge to design therapeutic strategies based on intervention.

描述（由申请人提供）：