Reference - Detail
| RRC ID | 87825 |
|---|---|
| Author | Etoh K, Hino Y, Morishita H, Nakao M. |
| Title | FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated secretory phenotype. |
| Journal | Mol Cell |
| Abstract |
The pro-inflammatory, senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells (SnCs) that exacerbates age-related pathophysiology and chronic diseases. Although unique gene regulation is essential for fulfilling the pro-inflammatory SASP, the epigenomic basis in SnCs remains largely unknown. Here, we show that FOXF1/2 define the senescence-specific enhancer landscape by shaping chromatin accessibility. FOXF1/2 interact with p300/CREB-binding protein (CBP) and stimulate H3K27 acetylation and chromatin opening at de novo enhancers of pro-inflammatory SASP genes, together with the recruitment of AP-1 c-JUN to these regions. FOXF1/2 depletion in SnCs significantly suppresses pro-inflammatory SASP, independent of persistent growth arrest, and diminishes the paracrine effect on surrounding cells. Notably, loss of FOXF1/2 leads to the redistribution of AP-1 c-JUN to regulatory elements of senescence-associated downregulated genes. Our results uncover that FOXF1/2 coordinate the pro-inflammatory SASP program, suggesting that FOXF1/2-mediated enhancer remodeling is a key target for modulating SnCs to promote healthy aging. |
| Volume | 86(8) |
| Pages | 1441-1458.e7 |
| Published | 2026-4-16 |
| DOI | 10.1016/j.molcel.2026.03.020 |
| PII | S1097-2765(26)00196-6 |
| PMID | 41997110 |
| MeSH | Acetylation Animals Cellular Senescence* / genetics Chromatin / genetics Chromatin / metabolism Chromatin Assembly and Disassembly Enhancer Elements, Genetic* Forkhead Transcription Factors* / genetics Forkhead Transcription Factors* / metabolism Gene Expression Regulation HEK293 Cells Histones / genetics Histones / metabolism Humans Inflammation* / genetics Inflammation* / metabolism Inflammation* / pathology Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism Senescence-Associated Secretory Phenotype* / genetics Transcription Factor AP-1 / genetics Transcription Factor AP-1 / metabolism p300-CBP Transcription Factors / genetics p300-CBP Transcription Factors / metabolism |
| IF | 15.584 |
| Resource | |
| DNA material | pMRX-puro-EGFP-Rab6A (RDB17361) |