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<p>The cohesin complex structures the interphase genome of human cells by extruding loops and organizing topologically associating domains (TADs), yet how chromatin state regulates cohesin-chromatin interactions remains unclear. Here, we show that histone hyperacetylation induced by trichostatin A (TSA) selectively disrupts short-range intra-TAD interactions while largely preserving CTCF-anchored loops. These distinct responses define two functional cohesin populations: a TSA-sensitive pool associated with dynamic loop extrusion, and a TSA-resistant pool at CTCF sites maintained by topological entrapment. Using a semi-in vitro system with TEV-cleavable RAD21, we demonstrate that hyperacetylation increases the sensitivity of CTCF-anchored loops to cohesin ring cleavage, supporting a topological basis for their stability. We further identify a TSA-sensitive cohesin fraction at CTCF sites, suggesting transient, non-encircling intermediates. Together, our results reveal that cohesin exists in distinct biochemical states that differentially regulate chromatin loop stability and responsiveness to epigenomic perturbation.</p>

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Histone Acetylation Differentially Modulates CTCF-CTCF Loops and Intra-TAD Interactions

  • 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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  • Rebecca G. Smith,
  • Yu Fu,
  • Kathleen L. Schiela,
  • Madison Dautle,
  • Ryan A. Williams,
  • Hannah M. Wilson,
  • Chloe Azadegan,
  • Johnathan R. Whetstine,
  • Job Dekker,
  • Yu Liu

摘要

The cohesin complex structures the interphase genome of human cells by extruding loops and organizing topologically associating domains (TADs), yet how chromatin state regulates cohesin-chromatin interactions remains unclear. Here, we show that histone hyperacetylation induced by trichostatin A (TSA) selectively disrupts short-range intra-TAD interactions while largely preserving CTCF-anchored loops. These distinct responses define two functional cohesin populations: a TSA-sensitive pool associated with dynamic loop extrusion, and a TSA-resistant pool at CTCF sites maintained by topological entrapment. Using a semi-in vitro system with TEV-cleavable RAD21, we demonstrate that hyperacetylation increases the sensitivity of CTCF-anchored loops to cohesin ring cleavage, supporting a topological basis for their stability. We further identify a TSA-sensitive cohesin fraction at CTCF sites, suggesting transient, non-encircling intermediates. Together, our results reveal that cohesin exists in distinct biochemical states that differentially regulate chromatin loop stability and responsiveness to epigenomic perturbation.