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<p>Dynamic genome folding is important for V(D)J recombination at the immunoglobulin kappa (<i>Igκ</i>) locus, which recombines Jκ and Vκ gene segments across a 3.2 Mb region in both deletional and inversional orientations. Chromatin loop extrusion and diffusion are considered two key mechanisms underlying <i>Igκ</i> locus folding, but how they coordinate remains unclear. Here we show that CTCF is a key regulator coupling loop extrusion and diffusion during <i>Igκ</i> V-J rearrangement, promoting recombination in both orientations across long genomic distances. Mechanistically, the CTCF N-terminus promotes long-range loop extrusion that facilitates distal Vκ usage by stabilizing cohesin against WAPL release, and also forms loop barriers enabling chromatin diffusion for inversional Vκ joining. In CTCF N-terminal-deficient B cells, defects in inversional Vκ joining are not restored by WAPL depletion but are instead largely rescued by a dCas9-blockade targeted to the Vκ-Jκ intergenic region, mimicking the CTCF barrier. Our findings thus highlight how CTCF coordinates distinct genome-folding mechanisms through its dual roles in cohesin stabilization and extrusion barrier formation to ensure the generation of a diverse <i>Igκ</i> repertoire.</p>

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CTCF couples long-range loop extrusion and diffusion to mediate a diverse Igκ repertoire

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Emma L. Bush,
  • Brigette Berke-Reynolds,
  • Kaitlyn M. Hutchins,
  • Xinrui Yu,
  • Jorge A. Colón-Rosado,
  • Fujung Chang,
  • John Curran,
  • Jiaxin Yang,
  • Liangliang Sun,
  • Jianrong Wang,
  • Yu Zhang

摘要

Dynamic genome folding is important for V(D)J recombination at the immunoglobulin kappa (Igκ) locus, which recombines Jκ and Vκ gene segments across a 3.2 Mb region in both deletional and inversional orientations. Chromatin loop extrusion and diffusion are considered two key mechanisms underlying Igκ locus folding, but how they coordinate remains unclear. Here we show that CTCF is a key regulator coupling loop extrusion and diffusion during Igκ V-J rearrangement, promoting recombination in both orientations across long genomic distances. Mechanistically, the CTCF N-terminus promotes long-range loop extrusion that facilitates distal Vκ usage by stabilizing cohesin against WAPL release, and also forms loop barriers enabling chromatin diffusion for inversional Vκ joining. In CTCF N-terminal-deficient B cells, defects in inversional Vκ joining are not restored by WAPL depletion but are instead largely rescued by a dCas9-blockade targeted to the Vκ-Jκ intergenic region, mimicking the CTCF barrier. Our findings thus highlight how CTCF coordinates distinct genome-folding mechanisms through its dual roles in cohesin stabilization and extrusion barrier formation to ensure the generation of a diverse Igκ repertoire.