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研究揭示染色质环挤出在抗体转型中的作用
2019-10-31 16:20

近日,美国波士顿儿童医院Frederick W. Alt及其小组揭示染色质环挤出在抗体转型中的基本作用。10月30日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员介绍,B淋巴细胞中的抗体转型重组(CSR)用位于下游100-200 kb的六个恒定区外显子(CH)之一取代了免疫球蛋白重链基因座(Igh)Cμ CH。每个CH的上游侧都有一个I型启动子和一个长重复转换(S)区域。细胞因子和激活蛋白引起的激活诱导胞苷脱氨酶(AID)和I型启动子转录,其中3'IgH调节区(3'IgHRR)增强子通过I型启动子竞争长距离3'IgHRR相互作用控制后者。通过供体Sμ和激活的下游受体S区进行转录,可将AID产生的脱氨损害靶向于数百个单独的S区域脱氨模体中的任何一个。一般的DNA修复途径将这些损害转变为双链断裂(DSB),并将Sμ上游DSB末端连接到受体S区域下游DSB末端,以删除CSR。分布于活化S区的AID启动的DSB靶点通常参与这种CSR缺失连接。

研究人员报道染色质环挤出是顺式IgH组织促进缺失CSR的机制的基础。在初始B细胞中,环挤出动态地将3'IgHRR增强子与200 kb上游Sμ并列,以生成CSR中心(CSRC)。在CSR激活的原代B细胞中,I型启动子转录激活cohesin加载,导致生成动态亚结构域,其将下游S区域与Sμ定向对齐以删除CSR。在CH12F3 B淋巴瘤细胞的组成型SαCSR期间,可以通过在挤出路径中插入基于CTCF结合元件(CBE)的障碍来激活反向CSR。CBE插入还通过抑制和促进CSSR中与Sμ的动态比对,使上游S区CSR失活,并将相邻的下游序列转化为异位S区。

这些发现表明,在CSSR中,动态阻碍cohesin介导的环挤出将AID起始的供体和受体S区DSB的正确末端并列,以进行缺失CSR。这种机制可能也有助于致病性DSB加入全基因组。

附:英文原文

Title: Fundamental roles of chromatin loop extrusion in antibody class switching

Author: Xuefei Zhang, Yu Zhang, Zhaoqing Ba, Nia Kyritsis, Rafael Casellas, Frederick W. Alt

Issue&Volume: 2019-10-30

Abstract: Antibody class switch recombination (CSR) in B lymphocytes replaces immunoglobulin heavy chain locus (Igh) C constant region exons (CHs) with one of six CHs lying 100200 kb downstream1. Each CH is flanked upstream by an I promoter and long repetitive switch (S) region1. Cytokines and activators induce activation-induced cytidine deaminase (AID)2 and I-promoter transcription, with 3 IgH regulatory region (3 IgHRR) enhancers controlling the latter via I-promoter competition for long-range 3 IgHRR interactions38. Transcription through donor S and an activated downstream acceptor S-region targets AID-generated deamination lesions at, potentially, any of hundreds of individual S-region deamination motifs911. General DNA repair pathways convert these lesions to double-stranded breaks (DSBs) and join an S-upstream DSB-end to an acceptor S-region-downstream DSB-end for deletional CSR12. AID-initiated DSBs at targets spread across activated S regions routinely participate in such deletional CSR joining11. Here we report that chromatin loop extrusion underlies the mechanism11 by which IgH organization in cis promotes deletional CSR. In naive B cells, loop extrusion dynamically juxtaposes 3 IgHRR enhancers with the 200-kb upstream S to generate a CSR centre (CSRC). In CSR-activated primary B cells, I-promoter transcription activates cohesin loading, leading to generation of dynamic subdomains that directionally align a downstream S region with S for deletional CSR. During constitutive S CSR in CH12F3 B lymphoma cells, inversional CSR can be activated by insertion of a CTCF-binding element (CBE)-based impediment in the extrusion path. CBE insertion also inactivates upstream S-region CSR and converts adjacent downstream sequences into an ectopic S region by inhibiting and promoting their dynamic alignment with S in the CSRC, respectively. Our findings suggest that, in a CSRC, dynamically impeded cohesin-mediated loop extrusion juxtaposes proper ends of AID-initiated donor and acceptor S-region DSBs for deletional CSR. Such a mechanism might also contribute to pathogenic DSB joining genome-wide. Chromatin loop extrusion has fundamental mechanistic roles in immunoglobulin heavy chain class switch recombination.

DOI: 10.1038/s41586-019-1723-0

Source:https://www.nature.com/articles/s41586-019-1723-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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