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<p>Activation-induced cytidine deaminase (AID)-initiated immunoglobulin heavy chain (<i>Igh</i>) class switch recombination (CSR) replaces donor Cμ constant region exons (C<sub>H</sub>s) with a downstream acceptor C<sub>H</sub> to generate different functional antibody isotypes. However, mechanisms governing orientation-specific productive CSR remain incompletely understood. Through analysing the characteristics of evolved constant regions and constructing diversified constant regions to recapitulate productive CSR in jawed vertebrates to systematically dissect productive CSR determinants, we find that switch topological configuration (STC), including transcriptional orientation, chromatin distance, and chromatin domain of <i>Igh</i>, determines orientation-specific joining of AID-initiated breaks for productive CSR. Long-distance C<sub>H</sub>s under co-oriented transcription within <i>Igh</i> domain foster predominantly deletional joining-mediated productive CSR. In contrast, oppositely transcribed and short-distance C<sub>H</sub>s affect end-joining bias via promoting diffusion-mediated inversional joining for CSR with lower efficiency. Moreover, AID-initiated breaks in different domains, facilitate more diffusion-mediated orientation-unbiased end-joining for non-productive CSR. Our findings uncover chromatin-intrinsic mechanisms safeguarding orientation-specific productive CSR throughout evolution.</p>

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Chromatin-intrinsic mechanisms determine orientation-specific class switch recombination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • Sha Luo,
  • Ruolin Qiao,
  • Hailiang Zha,
  • Leyi Yu,
  • Xiaoling Shan,
  • Shuchan Li,
  • Zifan Yang,
  • Aoyu Ma,
  • Yaxin Cheng,
  • Yao-Feng Zhao,
  • Xuefei Zhang

摘要

Activation-induced cytidine deaminase (AID)-initiated immunoglobulin heavy chain (Igh) class switch recombination (CSR) replaces donor Cμ constant region exons (CHs) with a downstream acceptor CH to generate different functional antibody isotypes. However, mechanisms governing orientation-specific productive CSR remain incompletely understood. Through analysing the characteristics of evolved constant regions and constructing diversified constant regions to recapitulate productive CSR in jawed vertebrates to systematically dissect productive CSR determinants, we find that switch topological configuration (STC), including transcriptional orientation, chromatin distance, and chromatin domain of Igh, determines orientation-specific joining of AID-initiated breaks for productive CSR. Long-distance CHs under co-oriented transcription within Igh domain foster predominantly deletional joining-mediated productive CSR. In contrast, oppositely transcribed and short-distance CHs affect end-joining bias via promoting diffusion-mediated inversional joining for CSR with lower efficiency. Moreover, AID-initiated breaks in different domains, facilitate more diffusion-mediated orientation-unbiased end-joining for non-productive CSR. Our findings uncover chromatin-intrinsic mechanisms safeguarding orientation-specific productive CSR throughout evolution.