Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer

Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, Reo Maruyama, Risa Fujii, Koji Ueda, Li Jiang, Hao Zheng, Shinya Toyokuni, Toyonori Sakata, Katsuhiko Shirahige, Ryosuke Kojima, Mizuho Nakayama, Masanobu Oshima, Satoshi NagayamaHiroyuki Seimiya, Toru Hirota, Hideyuki Saya, Eiji Hara, Akiko Takahashi

Research output: Contribution to journalArticlepeer-review


Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non-cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

Original languageEnglish
Article numbere2025647118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
Publication statusPublished - 2021 Aug 31


  • CTCF
  • Pericentromeric RNA
  • Senescence
  • Senescence-associated secretory phenotype
  • Small extracellular vesicles

ASJC Scopus subject areas

  • General


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