FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated...

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.