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Loop extrusion mediates physiological Igh locus contraction for RAG scanning

Author

Listed:
  • Hai-Qiang Dai

    (Boston Children’s Hospital
    Harvard Medical School)

  • Hongli Hu

    (Boston Children’s Hospital
    Harvard Medical School)

  • Jiangman Lou

    (Boston Children’s Hospital
    Harvard Medical School)

  • Adam Yongxin Ye

    (Boston Children’s Hospital
    Harvard Medical School)

  • Zhaoqing Ba

    (Boston Children’s Hospital
    Harvard Medical School)

  • Xuefei Zhang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Yiwen Zhang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Lijuan Zhao

    (Boston Children’s Hospital
    Harvard Medical School)

  • Hye Suk Yoon

    (Boston Children’s Hospital
    Harvard Medical School)

  • Aimee M. Chapdelaine-Williams

    (Boston Children’s Hospital
    Harvard Medical School)

  • Nia Kyritsis

    (Boston Children’s Hospital
    Harvard Medical School)

  • Huan Chen

    (Boston Children’s Hospital
    Harvard Medical School)

  • Kerstin Johnson

    (Boston Children’s Hospital
    Harvard Medical School)

  • Sherry Lin

    (Boston Children’s Hospital
    Harvard Medical School)

  • Andrea Conte

    (NIAMS, NIH
    Center of Cancer Research, NCI, NIH)

  • Rafael Casellas

    (NIAMS, NIH
    Center of Cancer Research, NCI, NIH)

  • Cheng-Sheng Lee

    (National Tsing Hua University, Institute of Molecular and Cellular Biology)

  • Frederick W. Alt

    (Boston Children’s Hospital
    Harvard Medical School)

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.

Suggested Citation

  • 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 , 2021. "Loop extrusion mediates physiological Igh locus contraction for RAG scanning," Nature, Nature, vol. 590(7845), pages 338-343, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7845:d:10.1038_s41586-020-03121-7
    DOI: 10.1038/s41586-020-03121-7
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    Citations

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    Cited by:

    1. Khalid H. Bhat & Saurabh Priyadarshi & Sarah Naiyer & Xinyan Qu & Hammad Farooq & Eden Kleiman & Jeffery Xu & Xue Lei & Jose F. Cantillo & Robert Wuerffel & Nicole Baumgarth & Jie Liang & Ann J. Feene, 2023. "An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jin H. Yang & Hugo B. Brandão & Anders S. Hansen, 2023. "DNA double-strand break end synapsis by DNA loop extrusion," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Louisa Hill & Gordana Wutz & Markus Jaritz & Hiromi Tagoh & Lesly Calderón & Jan-Michael Peters & Anton Goloborodko & Meinrad Busslinger, 2023. "Igh and Igk loci use different folding principles for V gene recombination due to distinct chromosomal architectures of pro-B and pre-B cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Li-Hsin Chang & Sourav Ghosh & Andrea Papale & Jennifer M. Luppino & Mélanie Miranda & Vincent Piras & Jéril Degrouard & Joanne Edouard & Mallory Poncelet & Nathan Lecouvreur & Sébastien Bloyer & Amél, 2023. "Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Shuai Liu & Yaqiang Cao & Kairong Cui & Qingsong Tang & Keji Zhao, 2022. "Hi-TrAC reveals division of labor of transcription factors in organizing chromatin loops," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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