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Loop extrusion mediates physiological Igh locus contraction for RAG scanning

机译：环路挤压介导抹布扫描的生理学IGH轨迹收缩

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摘要

RAG endonuclease initiates Igh V(D)J recombination in progenitor B cells by binding a J_(H)-recombination signal sequence (RSS) within a recombination centre (RC) and then linearly scanning upstream chromatin, presented by loop extrusion mediated by cohesin, for convergent D-RSSs~(1,2). The utilization of convergently oriented RSSs and cryptic RSSs is intrinsic to long-range RAG scanning~(3). Scanning of RAG from the DJ_(H)-RC-RSS to upstream convergent V_(H)-RSSs is impeded by D-proximal CTCF-binding elements (CBEs)~(2-5). Primary progenitor B cells undergo a mechanistically undefined contraction of the V_(H)locus that is proposed to provide distal V_(H)s access to the DJ_(H)-RC~(6-9). Here we report that an inversion of the entire 2.4-Mb V_(H)locus in mouse primary progenitor B cells abrogates rearrangement of both V_(H)-RSSs and normally convergent cryptic RSSs, even though locus contraction still occurs. In addition, this inversion activated both the utilization of cryptic V_(H)-RSSs that are normally in opposite orientation and RAG scanning beyond the V_(H)locus through several convergent CBE domains to the telomere. Together, these findings imply that broad deregulation of CBE impediments in primary progenitor B cells promotes RAG scanning of the V_(H)locus mediated by loop extrusion. We further found that the expression of wings apart-like protein homologue (WAPL)~(10), a cohesin-unloading factor, was low in primary progenitor B cells compared with v-Abl-transformed progenitor B cell lines that lacked contraction and RAG scanning of the V_(H)locus. Correspondingly, depletion of WAPL in v-Abl-transformed lines activated both processes, further implicating loop extrusion in the locus contraction mechanism.
机译：RAG成套核酸酶通过结合重组中心（RC）内的J_（H） - 份异混合信号序列（RS）然后线性扫描上游染色质，引发祖细胞B细胞中的Igh V（d）J重组，然后通过Coholy介导的环挤出，对于收敛的D-RSS〜（1,2）。趋于导向的RSS和Cryptic RSS的利用是远程RAG扫描〜（3）的内在型。从D-Proximal CTCF结合元素（CBE）〜（2-5）阻碍了从DJ_（H）-RC-RS的扫描到上游收敛v_（h）-rss。主要祖母B细胞经历了所提出的V_（H）轨迹的机械上未定义的收缩，该轨迹提供对DJ_（H）-RC〜（6-9）的远端V_（h）访问。在这里，我们报告的是，即使仍然发生轨迹收缩，鼠标一次祖母B细胞中的整个2.4-MB V_（H）轨迹的反转消除了V_（H）-RSSS和通常会聚隐秘RSSS的重新排列。此外，该反演激活了通常以相反的方向和RAG扫描的密码V_（H）-RSS的利用，通过几个会聚的CBE域到端子。这些研究结果暗示，初级祖细胞B细胞中CBE障碍的广泛放入放松促进由环挤出介导的V_（H）基因座的rag扫描。我们进一步发现，与缺乏收缩和抹布的V-Abl转化的祖细胞系相比，翅膀的翅膀状蛋白质同源物（WAPL）〜（10），幼粒 - 卸载因子的表达在初生祖细胞中较低扫描V_（h）轨迹。相应地，V-ABL变换线中的WAPL耗尽激活了两个过程，进一步暗示了轨迹收缩机制中的环路挤出。

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  • 来源
    《Nature》 |2021年第7845期|338-343|共6页
  • 作者

    Hai-Qiang Dai; Hongli Hu; Jiangman Lou; Adam Yongxin Ye; Zhaoqing Ba; Xuefei Zhang; Yiwen Zhang; Lijuan Zhao; Hye Suk Yoon; Aimee M Chapdelaine-Williams; Nia Kyritsis; Huan Chen; Kerstin Johnson; Sherry Lin; Andrea Conte; Rafael Casellas; Cheng-Sheng Lee; Frederick W Alt;

  • 作者单位

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

    Lymphocyte Nuclear Biology NIAMS|Center of Cancer Research NCI;

    Lymphocyte Nuclear Biology NIAMS|Center of Cancer Research NCI;

    Department of Life Science National Tsing Hua University Institute of Molecular and Cellular Biology;

    Howard Hughes Medical Institute Program in Cellular and Molecular Medicine Boston Children's Hospital|Department of Genetics Harvard Medical School;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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