Loop extrusion mediates physiological Igh locus contraction for RAG scanning

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 () and Frederick W. Alt ()
Additional contact information
Hai-Qiang Dai: Boston Children’s Hospital
Hongli Hu: Boston Children’s Hospital
Jiangman Lou: Boston Children’s Hospital
Adam Yongxin Ye: Boston Children’s Hospital
Zhaoqing Ba: Boston Children’s Hospital
Xuefei Zhang: Boston Children’s Hospital
Yiwen Zhang: Boston Children’s Hospital
Lijuan Zhao: Boston Children’s Hospital
Hye Suk Yoon: Boston Children’s Hospital
Aimee M. Chapdelaine-Williams: Boston Children’s Hospital
Nia Kyritsis: Boston Children’s Hospital
Huan Chen: Boston Children’s Hospital
Kerstin Johnson: Boston Children’s Hospital
Sherry Lin: Boston Children’s Hospital
Andrea Conte: NIAMS, NIH
Rafael Casellas: NIAMS, NIH
Cheng-Sheng Lee: National Tsing Hua University, Institute of Molecular and Cellular Biology
Frederick W. Alt: Boston Children’s Hospital

Nature, 2021, vol. 590, issue 7845, 338-343

Abstract: Abstract 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)2–5. Primary progenitor B cells undergo a mechanistically undefined contraction of the VH locus that is proposed to provide distal VHs access to the DJH-RC6–9. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03121-7

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