染色体循环挤出在抗体类别切换中的基本作用
Xuefei Zhang1,2,3, Yu Zhang1,2,3,4, Zhaoqing Ba1,2,3
1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
Nature
|November 1, 2019
概括
通过组织免疫球蛋白重链位点来驱动抗体类切换重组 (CSR). 这一过程调整了B细胞中有效基因编辑的DNA断裂,可能会影响全基因组的DNA修复.
科学领域:
- 免疫学
- 分子生物学
- 遗传学
背景情况:
- 抗体类切换重组 (CSR) 取代免疫球蛋白重链 (Igh) 常态区域的外因子,使B细胞能够产生具有不同功能的抗体.
- CSR涉及激活诱导的cytidine除氨酶 (AID) 和DNA修复途径,在交换机 (S) 区域内产生双链断裂 (DSB).
- 3'IgH调节区域 (3'IgHRR) 增强剂和I-促进体转录对于指导CSR至关重要.
研究的目的:
- 阐明染色体循环挤出促进Igh位点内的缺失CSR的机制.
- 研究凝聚力和动态子域在企业社会责任方面对S区域的作用.
- 探索CTCF绑定元件 (CBEs) 等循环挤出障碍如何影响CSR和S区域功能.
主要方法:
- 在原始和CSR激活的B细胞中研究了染色体组织和循环挤出动态.
- 使用CTCF绑定元件 (CBEs) 来阻碍特定S区域的循环挤出.
- 分析了循环挤出阻碍对B淋巴瘤细胞的删除和反转CSR的影响.
主要成果:
- 在原始B细胞中,染色体循环挤出动态地将3'IgHRR增强剂与Sμ相对应,形成一个CSR中心 (CSRC).
- 在CSR激活的细胞中,凝聚素介导的循环挤出产生了下游S区域与Sμ对齐的删除CSR.
- 通过改变CSRC内部的动态对齐,CBE插入会破坏正常的循环挤出,改变S区域的CSR并创建外宫S区域.
结论:
- 凝聚蛋白介导循环挤出是用于删除CSR的AID启动的DSB定位的一个基本机制.
- 动态循环挤出及其受到CBE等因素的阻碍调节了S区域对齐和企业社会责任的结果.
- 这些发现表明,循环挤出有助于目标的DSB结合,这对全基因组DNA修复有潜在影响.
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