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<p>Senescence, the endpoint of normal cells’ replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and functional purpose of SICCs remain unknown. Here we combine three-dimensional genomics, super-resolution imaging, DNA tracing and functional assays with modeling to dissect SICC emergence. We find that, on senescence entry, cells repurpose SRRM2—a key component of nuclear speckles—and BANF1—a ‘molecular glue’ for chromosomes—to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles helps instruct the senescence splicing program, because disruption of SICCs almost fully reverts alternative splicing patterns and delays senescence onset. We therefore uncover a paradigm whereby human cells translate changes in nuclear biochemistry into architectural changes directing splicing choices to commit to the fate of senescence.</p>

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Senescent cells cluster CTCF on nuclear speckles to instruct an alternative splicing program

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Spiros Palikyras,
  • Vassiliki Varamogiani-Mamatsi,
  • Yajie Zhu,
  • Athanasia Mizi,
  • Shyam Ramasamy,
  • Jonas Viken Grini,
  • Isabel Liebermann,
  • Athanasia Stavropoulou,
  • Andrés Penagos Puig,
  • Tuba Sena Ogurlu-Tank,
  • Konstantinos Kydonakis,
  • Ioanna Papadionysiou,
  • Deniz Bartsch,
  • Yulia Kargapolova,
  • Natalia Rosalia Morero,
  • Konstantinos Sofiadis,
  • Christoforos Nikolaou,
  • Franziska Kundel,
  • Leo Kurian,
  • Jan Ellenberg,
  • A. Marieke Oudelaar,
  • Mariano Barbieri,
  • Kai Sandvold Beckwith,
  • Argyris Papantonis

摘要

Senescence, the endpoint of normal cells’ replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and functional purpose of SICCs remain unknown. Here we combine three-dimensional genomics, super-resolution imaging, DNA tracing and functional assays with modeling to dissect SICC emergence. We find that, on senescence entry, cells repurpose SRRM2—a key component of nuclear speckles—and BANF1—a ‘molecular glue’ for chromosomes—to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles helps instruct the senescence splicing program, because disruption of SICCs almost fully reverts alternative splicing patterns and delays senescence onset. We therefore uncover a paradigm whereby human cells translate changes in nuclear biochemistry into architectural changes directing splicing choices to commit to the fate of senescence.