Mechanisms of condensin-mediated gene regulation in C. elegans

秀丽隐杆线虫凝缩蛋白介导的基因调控机制

• 批准号: 10810352
• 负责人: Sevinc Ercan
• 金额: $ 1.18万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10810352
• 关键词: Address; Affect; Binding; Caenorhabditis elegans; Cell division; Chromosome Condensation; Chromosome Segregation; Chromosome Structures; Chromosomes; Complex; Disease; Dosage Compensation (Genetics); Elements; Eukaryota; Experimental Models; Gene Expression Regulation; Genetic Transcription; Genome; Genomic approach; Genomics; Health; Hermaphroditism; Human; Interphase; Mediating; Molecular; Outcome; Play; Regulation; Regulator Genes; Regulatory Element; Site; Specificity; Structure; Work; X Chromosome; condensin; feature detection; gene repression; genetic approach; histone modification; imaging approach; model organism; protein complex; recruit; transcription factor

PROJECT SUMMARY/ABSTRACT Regulation of chromosome structure is fundamental for genome function. Across eukaryotes, a key regulator of chromosome structure is an evolutionarily conserved protein complex called condensin, which is essential for chromosome condensation and segregation during cell division and play key roles in gene regulation during interphase. The molecular mechanisms behind how condensins bind and regulate chromosome structure and how this affects transcription remain unclear. To address this, we use a specialized condensin that functions within the X chromosome dosage compensation complex (DCC) in C. elegans. DCC specifically binds to and represses transcription of both X chromosomes in hermaphrodites by a factor of two. The co-option of condensin for X chromosome dosage compensation provides a powerful experimental model to study the mechanisms that control specificity of condensin binding and to analyze condensin-mediated changes in chromosome structure and transcription with high precision, all free from potential indirect effects on chromosome segregation. Our previous work suggests that specific and robust DCC binding to the X chromosomes is accomplished by a step-wise recruitment mechanism followed by linear spreading. First, DCC enters the chromosome at a small number of X-specific sites defined by two genomic features: the presence of multiple 12-bp recruitment motifs and overlap with high occupancy transcription factor target sites. After X-specific entry, additional sites cooperate over long-distance to increase the level of DCC recruitment across the chromosome. From the recruitment sites, DCC spreads linearly along large chromosomal domains, accumulating at active gene regulatory elements across the X. DCC binding leads to chromosome-wide transcriptional repression, changes in the level of specific histone modifications, chromosome compaction, and long-range chromosomal interactions. Here, we will address several important questions regarding DCC recruitment, spreading and function using a powerful set of genetic, genomic and imaging approaches: 1) How does the DCC recognize features of the initial entry sites on the X? 2) What is the mechanism behind long-distance cooperation between DCC recruitment elements? 3) How is DCC spreading and DCC-mediated chromosomal interactions regulated? 4) What is the mechanism by which the DCC represses transcription? The outcome of our work will elucidate the basic molecular mechanisms by which condensins perform their wide-range of essential functions in eukaryotes. This is relevant to human health because condensin structure and function is deeply conserved from C. elegans to humans, and determining how condensins function is key to understanding the contribution of chromosome structure to genome function in health and disease.

项目摘要/摘要 染色体结构的调节是基因组功能的基础。在真核生物中，一个关键的调控因子 染色体结构是一种进化上保守的蛋白质复合体，称为凝集素，它对 染色体在细胞分裂过程中的凝聚和分离，在基因调控中起关键作用 间期。凝聚素结合和调节染色体结构的分子机制 目前还不清楚这是如何影响转录的。为了解决这一问题，我们使用了一种专门的凝聚器，它具有 在线虫X染色体剂量补偿复合体(DCC)内。DCC专门绑定到和 将两性人两条X染色体的转录抑制2倍。增选的 凝聚素用于X染色体剂量补偿为研究X染色体剂量补偿提供了有力的实验模型 控制凝聚素结合的特异性和分析凝聚素介导的变化的机制 高精度的染色体结构和转录，均不受潜在的间接影响 染色体分离。 我们以前的工作表明，特异和强大的DCC与X染色体的结合是通过一个 循序渐进的招募机制，然后是线性传播。首先，DCC以很小的比例进入染色体 由两个基因组特征定义的X特异位点的数量：存在多个12个碱基的招募基序 并与高占有率的转录因子靶点重叠。在特定于X的条目之后，其他站点 远距离合作，提高整个染色体上的DCC招募水平。从 募集部位，DCC沿着大的染色体区域线性传播，在活性基因处积累 跨X.DCC结合的调控元件导致染色体范围的转录抑制、变化 在特定的组蛋白修饰、染色体紧凑和远程染色体的水平上 互动。在这里，我们将讨论几个关于DCC招募、传播和 使用一套强大的遗传、基因组和成像方法来发挥功能：1)DCC如何识别 X上最初进入站点的特点？2)远程合作背后的机制是什么 在DCC招募元件之间？3)DCC如何扩散和DCC介导的染色体相互作用 调控？4)DCC抑制转录的机制是什么？ 我们的工作成果将阐明凝聚素执行其功能的基本分子机制 真核生物中广泛的基本功能。这与人类健康有关，因为凝集素结构 从线虫到人类，凝聚素的功能都是非常保守的，确定凝聚素的功能是关键 了解染色体结构在健康和疾病中对基因组功能的贡献。

项目成果

Hatched and starved: Two chromatin compaction mechanisms join forces to silence germ cell genome.

• DOI: 10.1083/jcb.202107026
• 发表时间: 2021-09-06
• 期刊: The Journal of cell biology
• 作者: Morao AK;Ercan S
• 通讯作者: Ercan S

Identification and prediction of developmental enhancers in sea urchin embryos.

• DOI: 10.1186/s12864-021-07936-0
• 发表时间: 2021-10-19
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Arenas-Mena C;Miljovska S;Rice EJ;Gurges J;Shashikant T;Wang Z;Ercan S;Danko CG
• 通讯作者: Danko CG