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Loop extrusion mediates physiological Igh locus contraction for RAG scanning
Nature ( IF 42.778 ) Pub Date : 2021-01-13 , DOI: 10.1038/s41586-020-03121-7
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

RAG endonuclease initiates Igh V(D)J recombination in progenitor B cells by binding a JH-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-RSSs1,2. The utilization of convergently oriented RSSs and cryptic RSSs is intrinsic to long-range RAG scanning3. Scanning of RAG from the DJH-RC-RSS to upstream convergent VH-RSSs is impeded by D-proximal CTCF-binding elements (CBEs)2,3,4,5. Primary progenitor B cells undergo a mechanistically undefined contraction of the VH locus that is proposed to provide distal VHs access to the DJH-RC6,7,8,9. Here we report that an inversion of the entire 2.4-Mb VH locus in mouse primary progenitor B cells abrogates rearrangement of both VH-RSSs and normally convergent cryptic RSSs, even though locus contraction still occurs. In addition, this inversion activated both the utilization of cryptic VH-RSSs that are normally in opposite orientation and RAG scanning beyond the VH 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 VH 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 VH locus. Correspondingly, depletion of WAPL in v-Abl-transformed lines activated both processes, further implicating loop extrusion in the locus contraction mechanism.



中文翻译:

环形挤压介导生理性Igh基因座收缩以进行RAG扫描

RAG核酸内切酶通过结合重组中心(RC)内的J H重组信号序列(RSS),然后线性扫描上游染色质(由粘着蛋白介导的环挤出法)以收敛祖细胞B中的Igh V(D)J重组。D-RSS 1,2。融合定向RSS和隐式RSS的使用是远程RAG扫描3固有的。从DJ H -RC-RSS到上游收敛V H -RSSs的RAG扫描受D-近端CTCF绑定元素(CBE)2,3,4,5的阻碍。原代祖细胞B发生机械不确定的V H收缩建议提供远端V H进入DJ H -RC 6,7,8,9的轨迹。在这里我们报告说,小鼠原代祖细胞中整个2.4 Mb V H基因座的倒置消除了V H -RSSs和通常会聚的隐性RSS的重排,即使基因座收缩仍然发生。另外,这种反演激活了通常沿相反方向的隐秘V H -RSS的利用和通过多个会聚CBE域到达端粒的RAG扫描超出V H基因座。总之,这些发现暗示原代祖细胞中CBE障碍的广泛解除促进了V H的RAG扫描环挤出介导的基因座。我们进一步发现,与缺乏收缩和RAG扫描的v-Abl转化的祖细胞B细胞系相比,原代祖细胞B中的鸡翅样蛋白同源物(WAPL)10(一种黏着素卸载因子)的表达较低。V H轨迹。相应地,在v-Abl转化的细胞系中WAPL的耗尽激活了两个过程,进一步牵涉了在基因座收缩机制中的环挤出。

更新日期:2021-01-13
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