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

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

细胞衰老（Cellular senescence）是一类与肿瘤抑制、伤口愈合及部分年龄相关病理状态密切相关的稳态程序。衰老细胞会呈现出抑制性染色质构型，该构型被认为可稳定沉默增殖促进基因，同时激活一种特殊的免疫监视过程，该过程涉及被称为衰老相关分泌表型（senescence-associated secretory phenotype, SASP）的分泌程序。本研究证实，细胞衰老还伴随增强子景观的全局重塑——染色质阅读器（chromatin reader）BRD4会被招募至关键SASP基因旁侧新激活的超级增强子（super-enhancers）中。转录谱分析与功能研究表明，BRD4是SASP形成及下游旁分泌信号通路发挥功能所必需的分子。据此，抑制BRD4可在体外与体内破坏免疫细胞介导的癌前衰老细胞靶向与清除过程。本研究结果揭示了结合BRD4的超级增强子在衰老免疫监视以及肿瘤抑制程序正常执行中的关键作用。整体实验设计：对处于增殖、静息或经HrasV12诱导的衰老状态的人成纤维细胞（IMR90）的RNA样本进行分析，所处理的细胞分别经Brd4、p65、p53、p53/RB、p16/21基因敲低，以及溶剂对照（Vehicle）和JQ1药物处理。