Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts.
Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts.
复制标题
衰老激活的增强子景观协调小鼠成纤维细胞中衰老相关的分泌表型
DOI：
10.1093/nar/gkaa858
复制
发表时间：
2020-11-04
影响因子：
14.9
通讯作者：
Tao W
中科院分区：
文献类型：
--
作者：
Guan Y;Zhang C;Lyu G;Huang X;Zhang X;Zhuang T;Jia L;Zhang L;Zhang C;Li C;Tao W
染色质结构的三维结构对转录网络的改变是至关重要的，然而，通过调节染色质结构来表观遗传控制衰老相关基因表达的潜在机制仍不清楚。在这里，我们证明了在小鼠胚胎成纤维细胞(MEF)复制衰老过程中，染色体室频繁切换，其特征是拓扑相关结构域(TADS)中的衰老失活(SIAE)和激活增强子(SAE)。从机制上讲，SAE与衰老相关的分泌表型(SASP)基因密切相关，SASP基因是衰老微环境的关键转录特征，有助于肿瘤进展、衰老加速和免疫炎症反应。此外，SAEs可以正向调节SASP表达的强健变化。转录因子CCAAT/增强子结合蛋白α(C/EBPα)能够增强SAE活性，加速SAE在SASP两侧的出现和下游因子的分泌，促进衰老。我们的结果揭示了染色质结构、转录因子和增强子活性在调节细胞衰老中的分级作用，从而为TAD相关的SASP基因表达调控提供了新的见解。
The three-dimensional configuration of the chromatin architecture is known to be crucial for alterations in the transcriptional network; however, the underlying mechanisms of epigenetic control of senescence-related gene expression by modulating the chromatin architecture remain unknown. Here, we demonstrate frequent chromosomal compartment switching during mouse embryonic fibroblasts (MEFs) replicative senescence as characterized by senescence-inactivated (SIAEs) and -activated enhancers (SAEs) in topologically associated domains (TADs). Mechanistically, SAEs are closely correlated with senescence-associated secretory phenotype (SASP) genes, which are a key transcriptional feature of an aging microenvironment that contributes to tumor progression, aging acceleration, and immunoinflammatory responses. Moreover, SAEs can positively regulate robust changes in SASP expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is capable of enhancing SAE activity, which accelerates the emergence of SAEs flanking SASPs and the secretion of downstream factors, contributing to the progression of senescence. Our results provide novel insight into the TAD-related control of SASP gene expression by revealing hierarchical roles of the chromatin architecture, transcription factors, and enhancer activity in the regulation of cellular senescence.
登录
查看更多内容
影响因子：
64.8
作者：
Jin, Fulai;Li, Yan;Dixon, Jesse R.;Selvaraj, Siddarth;Ye, Zhen;Lee, Ah Young;Yen, Chia-An;Schmitt, Anthony D.;Espinoza, Celso A.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
3.7
作者：
Coppé JP;Patil CK;Rodier F;Krtolica A;Beauséjour CM;Parrinello S;Hodgson JG;Chin K;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
64.5
作者：
Kim TK;Shiekhattar R
通讯作者：
Shiekhattar R
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.