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Transcriptional Regulation by Epigenetic Factors

表观遗传因素的转录调控

基本信息

批准号：
9915931
负责人：
ALEXANDER M MAZO
金额：
$ 31.98万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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：
2005-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915931
关键词：
Address Biological Biological Assay Cell Cycle Cell Differentiation process Cell division Cells Cellular Assay Chromatin Chromatin Structure Complex Conflict (Psychology)DNA DNA Polymerase II DNA biosynthesis DNA-Directed RNA Polymerase Data Daughter Development Disease Elongation Factor Ensure Epigenetic Process Foundations Future Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Health Heart Histones Kinetics Malignant Neoplasms Memory Microscopy Modeling Molecular Conformation Monitor Nature Normal Cell Nuclear Nucleosomes Pattern Play Process Proliferating Proteins Publishing RNA RNA Stability RNA chemical synthesis Regulatory Element Repression Research Resolution Role Solid TATA-Box Binding Protein Testing Time Transcriptional Elongation Factors Transcriptional Regulation Travel base cell regeneration daughter cell design drug discovery epigenetic regulation experimental study novel strategies programs protein complex recruit restoration stem cell differentiation stem cells theories transcription factor

项目摘要

Project Summary: Cell memory plays a key role during differentiation and disease. It relies on epigenetic inheritance that is essential to propagate gene expression program through cell generation, in large part through maintaining the structure of chromatin in daughter cell. DNA replication is the major obstacle in conservation of chromatin structure. During replication, most proteins are thought to dissociate from DNA. A few molecules may remain associated with DNA, thus marking DNA regulatory elements for future maturation of chromatin into an open or compact conformation. The identity of these epigenetic marks is unknown. The best candidates are thought to be modified histones because they are assumed to transfer from the parental to daughter nucleosomes on nascent DNA. However, until recently, there were no experimental approaches to directly examine neither the nature of epigenetic marks, nor the order and timing of recruitment of chromosomal proteins to DNA following replication. Similarly, we know very little about how and when transcription resumes after DNA replication. We developed several new experimental approaches that allow addressing these key epigenetic issues, and found that the structure of chromatin is not as severely disrupted as is currently suggested. RNA Polymerase II and related general transcription and elongation factors are found on nascent DNA just after replication. Moreover, even immature RNAs are found in the proximity to nascent DNA suggesting that the RNA Pol II – RNA complex is able to survive DNA replication. We also found that transcription resumes relatively quickly after DNA replication. Based on our published and preliminary results, we propose to test a new epigenetic concept suggesting that once transcription is established, most of the transcriptional apparatus may be associated with DNA through replication, thus serving as an epigenetic mark for active genes. This possibility, however, conflicts with the conventional model suggesting that transcription and replication complexes travel along DNA, since this will lead to collisions of these protein complexes. To resolve this contradiction, we will test the hypothesis that the stability of the transcriptional machinery through replication can be resolved if transcription and replication occur in the stationary nuclear sub-domains, transcription and replication factories, and that DNA is reeled through these protein factories. The results of these experiments will greatly contribute to our understanding of the epigenetic processes, and may have a major impact on developing new approaches in many biological and drug discovery fields.

项目总结: