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The role of Chd1 chromatin remodelers in the repression of pervasive transcription and dissecting the crosstalk between pervasive transcription, nucleosome positioning and turnover.

Chd1 染色质重塑剂在抑制普遍转录以及剖析普遍转录、核小体定位和周转之间的串扰中的作用。

基本信息

批准号：
284266649
负责人：
Dr. Tamás Fischer
金额：
--
依托单位：
College of Health and Medicine
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/284266649?language=en
关键词：
role Chd1 chromatin remodelers repression

项目摘要

The eukaryotic chromatin structure compacts and protects the genome but also limits the accessibility of the underlying DNA. Chromatin modifying activities can open the chromatin and provide regulated access to specific genomic loci. Chromatin characteristics, such as position, occupancy and turnover-rate of nucleosomes, establish an elaborate genomic indexing mechanism, which is responsible for defining functional units in the genome. Defects in this process lead to increased transcription outside of genetically defined transcription units, toxic accumulation of non-coding transcripts and genomic instability. However, how genomic indexing mechanisms accurately define transcription units and their transcripts is one of the fundamental questions in chromatin biology. The aims of this proposal are: (i) to understand the relationship between nucleosome position, turnover and repression of pervasive transcription; and (ii) to investigate the mechanism by which Chd1 maintains nucleosome arrays in gene coding regions with uniform, species-specific nucleosome distance. We will use various Schizosaccharomyces pombe (S. pombe) mutants that show increased cryptic promoter activity and determine the chromatin characteristics that are critical for repressing transcription initiation outside of the promoter regions. We plan to generate various Chd1 deletion and point mutants to dissect the crosstalk between nucleosome positioning, turnover and pervasive transcription and to further understand the role of Chd1 in these processes. Since the length of the linker DNA between nucleosomes varies widely between species, we will compare nucleosome arrays generated by Chd1-type enzymes from S.pombe (typical linker DNA length, 6 bp), Chaetomium thermophilum (typical linker DNA length, 26 bp) and various chimera proteins and test their effect on pervasive transcription and higher order chromatin structure. These studies will significantly increase our understanding of the eukaryotic genome-organization and the role of the chromatin in the definition of functional units in the genome. Disturbing this highly conserved structure leads to increased pervasive transcription activity and to genomic instability, which is a major cause of cancer development and aging. Increased understanding of the molecular mechanisms behind these processes may have important long-term therapeutic implications.

真核染色质结构压缩并保护基因组，但也限制了底层 DNA 的可及性。染色质修饰活性可以打开染色质并提供对特定基因组位点的受调控通路。染色质特征，例如核小体的位置、占据和周转率，建立了复杂的基因组索引机制，负责定义基因组中的功能单元。这一过程中的缺陷会导致遗传定义的转录单位之外的转录增加、非编码转录物的毒性积累和基因组不稳定。然而，基因组索引机制如何准确定义转录单位及其转录本是染色质生物学的基本问题之一。该提案的目的是：（i）了解核小体位置、周转和普遍转录抑制之间的关系； (ii) 研究 Chd1 在基因编码区维持核小体阵列具有均匀、物种特异性核小体距离的机制。我们将使用各种粟酒裂殖酵母 (S. pombe) 突变体，这些突变体显示出增加的隐性启动子活性，并确定对于抑制启动子区域外的转录起始至关重要的染色质特征。我们计划生成各种 Chd1 缺失和点突变体，以剖析核小体定位、周转和普遍转录之间的串扰，并进一步了解 Chd1 在这些过程中的作用。由于物种之间核小体之间的接头 DNA 长度差异很大，我们将比较由来自裂殖酵母（典型接头 DNA 长度，6 bp）、嗜热毛壳菌（典型接头 DNA 长度，26 bp）和各种嵌合蛋白的 Chd1 型酶产生的核小体阵列，并测试它们对普遍转录和高阶染色质结构的影响。这些研究将显着增加我们对真核基因组组织以及染色质在基因组功能单元定义中的作用的理解。扰乱这种高度保守的结构会导致普遍转录活性增加和基因组不稳定，这是癌症发展和衰老的主要原因。增加对这些过程背后的分子机制的了解可能具有重要的长期治疗意义。