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Accession IconSRP065206

BRD4 connects enhancer remodeling to senescence immune surveillance (RNA-seq)

Organism Icon Homo sapiens
Sample Icon 72 Downloadable Samples
Technology Badge IconIllumina HiSeq 2500

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Cellular senescence is a homeostatic program associated with tumor suppression, wound healing, and certain age related pathologies. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while at the same time activate an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell-mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program. Overall design: Analysis of RNA isolated from human fibroblasts (IMR90) in proliferating, quiescent or senescent (HrasV12) conditions upon knockdown of Brd4, p65, p53, p53/RB, p16/21 or Vehicle and JQ1 treatment
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