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Toward a Central Question in Epigenetics: A Major Epigenetic Programming Mechanis

表观遗传学的一个核心问题：主要的表观遗传编程机制

基本信息

批准号：
8699168
负责人：
Haifan Lin
金额：
$ 82.42万
依托单位：
YALE UNIVERSITY
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：
2010-09-30 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699168
关键词：
Accounting Affect Animals Base Pairing Binding Binding Sites Biological Assay Biomedical Research Cell Maintenance Cell physiology Cells ChIP-seq Chimeric Proteins Chromatin Chromosomes, Human, Pair 7 Co-Immunoprecipitations Complex DNA Data Degenerative Disorder Development Dimensions Disease Double-Stranded RNA Drosophila genome Drosophila genus Epigenetic Process Eukaryota Evolution Eye Color Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genome Genome Mappings Genomics Heterochromatin Human LacZ Genes Lead Maps Mediating Medicine Modeling Molecular Genetics Mutate Mutation Organism Plants Play Production Proteins RNA RNA Polymerase II Recruitment Activity Regulation Reporter Genes Research Resolution Ribonucleases Role Site Stem cells System Testing Transcript Transgenes Transgenic Organisms Work abstracting base cancer prevention cancer therapy chromosome mutation deep sequencing design epigenome fascinate fly frontier genome-wide histone methyltransferase histone modification human embryonic stem cell in vivo mutant novel novel strategies nuclease piRNA pluripotency programs promoter stem cell biology success theories

项目摘要

DESCRIPTION Abstract: Epigenetics represents an exciting new frontier of biomedical research. A central yet essentially unexplored question in epigenetics is how epigenetic regulators are directed to specific loci in the genome to exert their function. It is known that a few transcriptional factors can recruit certain epigenetic factors to the promoters of target genes. However, this mechanism so far can only account for a handful of genes, and a tiny fraction of the genome. The latest Drosophila work in my lab suggest that PIWI-interacting RNAs (piRNAs) play a major and direct role in guiding epigenetic factors to many sites in the genome. Particularly, piRNA form complexes with PIWI proteins and directly bind to piRNA-complementary sites in the genome to regulate their epigenetic state. Furthermore, we have shown that PIWI directly recruits a key epigenetic factor called Heterochromatin Protein 1a to these sites. Based on these results, we propose a "Piwi-piRNA guidance hypothesis", in which the Piwi-piRNA complex serves as a sequence- recognition machinery that recruits epigenetic effectors to specific genomic sites to execute epigenetic regulation. Here we propose to use combined genetic and genomic approaches to systematically test this hypothesis and to determine the contribution of the PIWI-piRNA- mediated mechanism to the genome at 10-basepair resolution. Specifically, we propose to: (1) Create the first functional epigenome map to determine the specific epigenetic effect of PIWI towards different regions of the genome; (2) develop a genome-wide epigenetic assay to examine the sufficiency and direct role of PIWI in regulating the transcriptional state of chromatin; and (3) take a four-pronged approach to directly test the role of piRNAs in guiding epigenetic factors to their sites. The proposed study should reveal a fascinating dimension of epigenetic regulation and generate a potentially transformative impact to the broad fields of epigenetics, genetics, molecular, developmental, and stem cell biology.

描述