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<p>Recent progress in statistical and experimental fine mapping of disease risk variants prompts us to focus on specific target loci for functional investigation. However, current genetics is hindered by a limited toolbox for target-loci analysis. To address this, we present UNIChro-seq, a method that digitally counts accessible chromatin molecules at target loci. UNIChro-seq allows for accurate, sensitive, and efficient quantification of allelic effects compared to conventional methods. Using UNIChro-seq, we investigate the effects of 57 autoimmunity risk alleles on chromatin accessibility and estimate the causal effects of 20 artificial variants generated through genome editing. As a caveat, a non-negligible fraction of the edited alleles exhibits a falsely positive effect on chromatin accessibility, which can be effectively distinguished from the true causal effect through bi-directional genome editing. Finally, functional dissection of a fine-mapped risk variant at the <i>LEF1</i> locus illuminates its relevance to T cell dysregulation in rheumatoid arthritis. Together, these findings underscore the utility of combining UNIChro-seq with genome editing technology to enable precise and scalable functional analysis of disease-associated loci.</p>

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Accurate, sensitive, and efficient chromatin accessibility quantification at target loci using UNIChro-seq

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月20日

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  • Michihiro Kono,
  • Hiroaki Hatano,
  • Kenichiro Asahara,
  • Masahiro Nakano,
  • Reza Bagherzadeh,
  • Tsugumi Kawashima,
  • Takahiro Arakawa,
  • Miho Sato,
  • Hajime Inokuchi,
  • Takahiro Nishino,
  • Takahiro Itamiya,
  • Haruka Takahashi,
  • Bunki Natsumoto,
  • Akari Suzuki,
  • Kazuhiko Yamamoto,
  • Kazuyoshi Ishigaki

摘要

Recent progress in statistical and experimental fine mapping of disease risk variants prompts us to focus on specific target loci for functional investigation. However, current genetics is hindered by a limited toolbox for target-loci analysis. To address this, we present UNIChro-seq, a method that digitally counts accessible chromatin molecules at target loci. UNIChro-seq allows for accurate, sensitive, and efficient quantification of allelic effects compared to conventional methods. Using UNIChro-seq, we investigate the effects of 57 autoimmunity risk alleles on chromatin accessibility and estimate the causal effects of 20 artificial variants generated through genome editing. As a caveat, a non-negligible fraction of the edited alleles exhibits a falsely positive effect on chromatin accessibility, which can be effectively distinguished from the true causal effect through bi-directional genome editing. Finally, functional dissection of a fine-mapped risk variant at the LEF1 locus illuminates its relevance to T cell dysregulation in rheumatoid arthritis. Together, these findings underscore the utility of combining UNIChro-seq with genome editing technology to enable precise and scalable functional analysis of disease-associated loci.