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绝缘子EACBE通过调节染色质组织来调控Tcrd基因的V(D)J重组。

The insulator EACBE regulates V(D)J recombination of Tcrd gene by modulating chromatin organization.

作者信息

Zhu Yongchang, Dai Ranran, Zhao Hao, Luo Junwei, Li Keyi, Xue Wei, Qin Litao, Pan Hongyuan, Liao Shixiu, Hao Bingtao

机构信息

Henan Key Provincial Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

出版信息

Front Immunol. 2025 Jul 17;16:1613621. doi: 10.3389/fimmu.2025.1613621. eCollection 2025.

Abstract

T cell receptor (TCR) diversity, essential for the recognition of a wide array of antigens, is generated through V(D)J recombination. The and genes reside within a shared genomic locus, with rearrangement occurring first in the double-negative (DN) stage during thymocyte development. Elucidating the regulatory mechanisms governing rearrangement is therefore crucial for understanding the developmental coordination of both and rearrangements. Chromatin architecture, orchestrated by CTCF-cohesin complexes and their binding sites, plays a fundamental role in regulating V(D)J recombination of antigen receptor genes. In this study, we report that EACBE, a CTCF binding element (CBE) located downstream of the - locus, regulates rearrangement. EACBE promotes the usage of proximal V gene segments by facilitating spatial proximity between the recombination centre and these V elements. Notably, EACBE counteracts the insulating effects of INTs, two CBEs that demarcate the proximal V region from the D-J-C cluster, thereby enabling effective chromatin extrusion. Furthermore, EACBE indirectly shapes the repertoire through its influence on rearrangement. These findings reveal a novel regulatory axis involving special chromatin configuration and highlight distinct roles for specific CTCF binding sites in modulating antigen receptor gene assembly.

摘要

T细胞受体(TCR)多样性对于识别多种抗原至关重要,它通过V(D)J重组产生。β和γ基因位于一个共享的基因组位点内,β重排在胸腺细胞发育的双阴性(DN)阶段首先发生。因此,阐明控制β重排的调控机制对于理解β和γ重排的发育协调性至关重要。由CTCF-黏连蛋白复合物及其结合位点精心编排的染色质结构,在调节抗原受体基因的V(D)J重组中起着基本作用。在本研究中,我们报告称EACBE,一个位于β基因座下游的CTCF结合元件(CBE),调节β重排。EACBE通过促进β重组中心与这些V元件之间的空间接近性,促进近端V基因片段的使用。值得注意的是,EACBE抵消了INTs(两个将近端V区域与D-J-C簇区分开的CBE)的绝缘作用,从而实现有效的染色质挤压。此外,EACBE通过其对β重排的影响间接塑造γ库。这些发现揭示了一个涉及特殊染色质构型的新型调控轴,并突出了特定CTCF结合位点在调节抗原受体基因组装中的不同作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6beb/12310595/d9fb9c1e80c5/fimmu-16-1613621-g001.jpg

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