TEAD4 delays cellular senescence by remodeling chromatin accessibility at H3K27ac-occupied enhancer regions [CUT&Tag]

Dramatic alterations in epigenetic landscapes are known to affect genome accessibility and their transcriptional program. Extensive evidences have emerged that senescent cells accumulate profound chromatin tremendous reordering upon senescence entry, yet, the underlying mechanisms between epigenetic parameters and gene expression profile have not been fully clarified. In this report, we delineate the genome-wide redistribution of accessible chromatin regions leading to broad transcriptome effects during UC-MSCs senescence. We report the distinct senescence-activated accessibility regions (SAAs) are always distributed in H3K27ac decorated enhancer regions, where the SAAs are responsible for elevated flanking SASP expression and aberrant cellular signaling relevant to SASP secretion. Mechanistically, a single transcription factor, TEAD4, shifting away from H3K27ac-labled SAAs and leading to prominent chromatin accessibility reconstruction during senescence. The enhanced signal of SAAs driven by TEAD4 suppression subsequently induce a robust decrease of adjacent SASP genes expression and downstream factors secretion, and finally, contributing to the progression of senescence. Our findings illustrate a dynamic landscape of chromatin accessibility following senescence entry and reveal an insightful function for TEAD4 in regulating the broad chromatin state that modulate the overall transcriptional program of the SASP genes. CUTTag analysis