Transcription-driven cohesin accumulation is associated with secretory phenotype of senescence [HiC]. Transcription-driven cohesin accumulation is associated with secretory phenotype of senescence [HiC]

Senescence is a stable form of cell cycle arrest that is triggered in response to various pathophysiological stimuli. The three-dimensional structure of senescent cells has been previously characterised, mostly in terms of macro-domains or changes between large heterochromatic regions. In the present body of work, using a combination of HiC and targetted Capture Hi-C, we aimed to investigate the association between gene expression and local chromatin structure in senescence, particularly focusing on enhancer-promoter (EP) interactions. We show that many EP contacts are rewired in RAS-induced Senescence compared to ‘normal’, growing cells and that these are associated with cohesin binding changes and possible loop re-organisation. The genes affected by altered chromatin interactions correspond to the two main axes of senescence gene regulation: cell cycle and inflammation. Our findings are potentially relevant during ageing and in cancers with cohesin mutations, where cell cycle and inflammation are also deregulated. Overall design: HiC and Capture HiC of growing and (RAS-induced) senescent IMR90 fibroblasts

细胞衰老是一种稳定的细胞周期阻滞状态，可由多种病理生理刺激因素诱发。此前已有研究对衰老细胞的三维结构开展了表征，相关分析多聚焦于宏观结构域或大型异染色质区域间的动态变化。本研究结合高通量染色体构象捕获（HiC）与靶向捕获HiC（Capture HiC）两种技术，旨在探究细胞衰老过程中基因表达与局部染色质结构的关联，尤其聚焦于增强子-启动子（enhancer-promoter, EP）相互作用。研究发现，与‘正常’增殖细胞相比，RAS诱导的衰老细胞中存在大量增强子-启动子相互作用的重连现象，且该现象与黏连蛋白结合模式改变及染色质环的潜在重构密切相关。受染色质相互作用改变影响的基因，对应细胞衰老基因调控的两大核心轴：细胞周期与炎症反应。本研究结果或与衰老进程及携带黏连蛋白突变的癌症相关——此类癌症中细胞周期与炎症反应同样存在调控紊乱。实验设计方案：对增殖状态及（RAS诱导的）衰老型IMR90成纤维细胞开展HiC与捕获HiC测序。