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

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

Automated summary

Cellular senescence leads to changes in chromatin organization and increased expression of inflammatory genes, affecting various age-related pathologies through SASP. Pericentromeric ncRNA impairs CTCF DNA binding, activating transcription of SASP-like inflammatory genes and promoting malignant transformation. The transfer of pericentromeric ncRNA through small extracellular vesicles contributes to a cell-autonomous and non-cell-autonomous SASP-like inflammatory response.