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Topological Control of Antigen Receptor Loci during Lymphocyte Development

淋巴细胞发育过程中抗原受体位点的拓扑控制

基本信息

批准号：
10238038
负责人：
CRAIG H BASSING
金额：
$ 73.1万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238038
关键词：
Antigen Receptors Architecture Binding Boundary Elements Cell Nucleus Chromatin Clinical Management Collaborations Communication Consensus DNA Data Defect Development Disease Elements Enhancers Event Foundations Gene Expression Gene Expression Regulation Genes Genetic Recombination Genetic Transcription Genome Hi-C Human Genome Individual Lead Link Logic Lymphocyte Lymphocyte antigen Modeling Molecular Molecular Conformation Monitor Mus Mutation Physiological Play Receptor Gene Regulation Regulator Genes Regulatory Element Research Resolution Shapes Site Spottings Stretching Structure T Chain T cell differentiation T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymocyte Development Time Tissues Transcriptional Activation Variant base cell type chromatin modification cohesin comparative driving force genome-wide analysis human disease in vivo infancy insight interest mammalian genome novel novel therapeutics physiologic model programs promoter three dimensional structure transcription factor

项目摘要

ABSTRACT Gene expression relies on interplay among cis elements, chromatin domains, and genome architecture. The latter is of intense interest as ~10% of human diseases may arise from defects in genome topology that impact gene expression. Genomes divide into conserved, Mb-sized topologically associated domains (TADs) that are further subdivided into cell type-specific loops between promoter and enhancers (regulatory loops) or between CTCF binding elements (structural loops). In addition, chromatin architecture can be shaped by tissue-specific boundary elements (BEs) that divide active and inactive regions of transcription. These two types of domains tend to associate spatially, perhaps through homotypic chromatin interactions. Foundational questions remain about mechanisms of genome architecture reorganization and its impact on gene expression during cellular differentiation. Answers to these questions have important implications because disease-associated variants in the human genome can disrupt CTCF sites or BEs, enabling aberrant communication between enhancers and alternative promoters that normally partition into separate architectural domains. The co-PIs have approached relationships between genome topology and gene regulation by focusing on the mouse Tcrb antigen receptor locus for several reasons, including: (i) it is a physiological model of manageable complexity (ii) its architecture and transcription are dynamically regulated during T cell development, (iii) it divides into alternating chromatin domains, (iv) changes in topology and transcription are critical for Tcrb assembly by long-range recombination, and (v) its recombination center (RC) has a simple regulatory landscape with one enhancer that communicates with two promoters to initiate all aspects of Tcrb assembly. The PIs' recent collaborations have provided important clues into the dynamics of Tcrb structure at a low level of resolution, but insights into mechanisms that sculpt the observed architectural changes are still lacking. These and other data support their hypothesis that developmental switches between inactive and active Tcrb conformations are orchestrated by tissue- and stage-specific changes in the binding of CTCF to cornerstone elements and by the transcription status of individual gene segments, which cooperate to compartmentalize Tcrb into distinct structural domains and drive homotypic interactions that facilitate long-range Tcrb gene assembly. To test foundational aspects of their hypothesis, the PIs propose to elucidate detailed topologies of active versus inactive Tcrb loci (Aim 1), assess whether transcription status and homotypic chromatin interactions shape Tcrb conformations (Aim 2), and determine mechanisms by which CTCF elements direct Tcrb topology (Aim 3). The co-PIs will monitor multiple physiological readouts (topology, transcription, chromatin, and recombination) to gain unprecedented insights into mechanistic relationships among genome architecture, gene expression, DNA recombination, and factors that sculpt primary lymphocyte antigen receptor gene repertoires

摘要基因表达依赖于顺式元件、染色质结构域和基因组结构之间的相互作用。的后者是非常感兴趣的，因为约10%的人类疾病可能是由基因组拓扑结构的缺陷引起的，基因表达。基因组分为保守的，Mb大小的拓扑相关结构域（TADs），进一步细分为启动子和增强子之间的细胞类型特异性环（调节环）或 CTCF结合元件（结构环）。此外，染色质结构可以通过组织特异性的边界元件（BE），划分转录的活性和非活性区域。这两种类型的域可能通过同型染色质相互作用而在空间上相关联。基础问题依然存在关于基因组结构重组的机制及其对细胞周期中基因表达的影响，分化这些问题的答案具有重要的意义，因为疾病相关的变异，人类基因组可以破坏CTCF位点或BE，使增强子之间的异常通讯成为可能，替代启动子，其通常划分为单独的结构域。联合私家侦探已经接近以小鼠Tcrb抗原受体为中心探讨基因组拓扑结构与基因调控的关系基因座的原因有几个，包括：（i）它是一个生理模型的可管理的复杂性（ii）其架构和转录在T细胞发育过程中受到动态调节，（iii）它分成交替的染色质结构域，（iv）拓扑结构和转录的变化对于Tcrb通过远程重组组装是至关重要的，和（v）其重组中心（RC）具有简单的调控景观，具有一个增强子，用两个启动子启动Tcrb组装的所有方面。PI最近的合作提供了在低分辨率水平下，Tcrb结构动力学的重要线索，仍然缺乏能够塑造所观察到的建筑变化的材料。这些和其他数据支持他们的假设非活性和活性Tcrb构象之间的发育转换是由组织协调的， CTCF与基石元件结合的阶段特异性变化以及单个基因片段，其合作将Tcrb区室化为不同的结构域，并驱动Tcrb的表达。促进长距离Tcrb基因组装的同型相互作用。来测试他们的假设，PI建议阐明活性与非活性Tcrb基因座的详细拓扑结构（目的1），评估转录状态和同型染色质相互作用是否塑造Tcrb构象（Aim 2），以及确定CTCF元素引导Tcrb拓扑的机制（目标3）。共同首席研究员将监控多个生理读数（拓扑结构，转录，染色质和重组），以获得前所未有的见解基因组结构、基因表达、DNA重组和因子之间的机械关系塑造了初级淋巴细胞抗原受体基因库

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Cyclin D3 Protein Enforces Monogenic TCRβ Expression by Mediating TCRβ Protein-Signaled Feedback Inhibition of Vβ Recombination.

细胞周期蛋白 D3 蛋白通过介导 Vβ 重组的 TCRβ 蛋白信号反馈抑制来强制单基因 TCRβ 表达。

DOI：
发表时间：
2024
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Culberson,EricaJ;Shields,KymberleC;Glynn,RebeccaA;Allyn,BrittneyM;Hayer,KatharinaE;Bassing,CraigH
通讯作者：
Bassing,CraigH

From RAG2 to T Cell Riches and Future Fortunes.

从 RAG2 到 T 细胞财富和未来财富。