Factors that regulate chromatin organization and gene transcription

调节染色质组织和基因转录的因素

基本信息

批准号：
9011537
负责人：
Brian D Strahl
金额：
$ 28.62万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9011537
关键词：
Address Animal Model Biochemistry Biology C-terminal Cell Cycle Cell Cycle Progression Centromere Chromatin Chromatin Structure Chromosomal Stability Code DNA biosynthesis Defect Deposition Euchromatin Evolution Excision Genes Genetic Genetic Transcription Genome Goals Health Heart Heterochromatin Histone Deacetylase Histone H3 Histones Human Human Development Laboratories Lysine Maintenance Malignant Neoplasms Mediating Methylation Molecular Chaperones N-terminal Nucleic Acid Regulatory Sequences Nucleosomes Pattern Phase Phosphorylation Play Post-Translational Protein Processing Process Proteins RNA Polymerase II Recruitment Activity Regulation Role S Phase Saccharomyces cerevisiae Site Staging Transcription Elongation Transcriptional Regulation Ubiquitin Variant Yeasts casein kinase II chromatin remodeling genome integrity human disease novel public health relevance repaired termination factor transcription termination ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT How chromatin domains such as euchromatin and heterochromatin are established and maintained are poorly understood. At the heart of chromatin organization are the histone proteins, which are deposited and removed by chaperone proteins. One such chaperone is Spt6, which is evolutionarily conserved and promotes transcription elongation through its interaction with the RNA polymerase II (RNAPII) C-terminal domain (CTD). During transcription, Spt6 mediates nucleosome reassembly in the wake of transcribing RNAPII and promotes H3K36 methylation, which recruits histone deacetylase and chromatin remodeling activities that maintain chromatin integrity in the coding region of genes. Our studies have now identified Spt6 as a central component of a novel regulatory circuit that maintains CTD phosphorylation; this circuit is itself controlled through Spt6 protein stability. We have also found that Spt6 is up-regulated during S phase, where it likely contributes to histone gene transcription and/or deposition at this critical stage. Further, we have uncovered an unexpected role for Spt6 in maintaining centromere identity through the potential targeting of the Psh1 E3 ligase that removes ectopically deposited histone H3 variant Cse4. Despite these findings, we know little about how Spt6 performs its chromatin-dependent activities. Thus, this proposal aims to elucidate the fundamental mechanisms by which Spt6 contributes to the maintenance of chromatin structure in the coding and regulatory regions of the genome - thereby contributing to the biology of Spt6 and to the mechanisms by which chromatin domains are established and maintained. To accomplish this goal, we will address the following key questions: 1) How is Spt6 regulated through its interactions with RNAPII and by post-translational modifications that occur on this protein? 2) Why is Spt6 cell cycle regulated, and what role does it play in S phase? 3) Does Spt6 function outside of its canonical role in transcriptional regulation to regulate other aspects of chromatin biology, in particular centromere identity? Given the conservation of Spt6 across evolution, our studies will significantly impact our understanding of the mechanisms that underlie transcriptional elongation and the maintenance of chromatin integrity that govern genome integrity. These studies will also be relevant to our understanding of Spt6 in human development and disease.

描述（由申请人提供）：抽象对染色质结构域（例如斑塑素和异染色质）的建立和维持方式很少。染色质组织的核心是组蛋白蛋白，这些蛋白是由伴侣蛋白沉积和去除的。这样的伴侣是SPT6，它是进化保守的，并通过与RNA聚合酶II（RNAPII）C末端结构域（CTD）的相互作用来促进转录伸长。在转录过程中，SPT6在转录RNAPII并促进H3K36甲基化后介导核小体重新组装，该甲基化募集了组蛋白脱乙酰基酶和染色质重塑活性，这些活性在基因编码区域中维持染色质完整性。现在，我们的研究将SPT6确定为维持CTD磷酸化的新调节回路的核心组成部分。该电路本身是通过SPT6蛋白稳定性控制的。我们还发现，在S相中，SPT6在S阶段被上调，在此关键阶段，它可能有助于组蛋白基因转录和/或沉积。此外，我们通过潜在的PSH1 E3连接酶的潜在靶向去除异位沉积的组蛋白H3变体CSE4来揭示了SPT6在维持着丝粒身份中的意外作用。尽管有这些发现，我们对SPT6如何执行其染色质依赖性活性知之甚少。因此，该提案旨在阐明SPT6在基因组的编码和调节区中维持染色质结构的基本机制，从而有助于SPT6的生物学以及建立和维持染色质领域的机制。为了实现这一目标，我们将解决以下关键问题：1）SPT6如何通过其与RNAPII的相互作用以及该蛋白质上发生的翻译后修饰来调节？ 2）为什么SPT6细胞周期受调节，在S阶段起什么作用？ 3）SPT6在转录调节中的规范作用以外的功能是否在调节染色质生物学的其他方面，特别是Centromere身份？鉴于SPT6在进化过程中的保护，我们的研究将极大地影响我们对基于转录伸长和维持基因组完整性的染色质完整性的机制的理解。这些研究也将与我们在人类发展和疾病中对SPT6的理解有关。