EZH2 reduction is an essential mechanoresponse for the maintenance of super-enhancer polarization against compressive stress in human periodontal ligament stem cells
EZH2 reduction is an essential mechanoresponse for the maintenance of super-enhancer polarization against compressive stress in human periodontal ligament stem cells
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EZH2 减少是维持人牙周膜干细胞抗压应力的超级增强器极化的重要机械反应
DOI：
10.1038/s41419-020-02963-3
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发表时间：
2020-09
影响因子：
9
通讯作者：
Zhang Yu
中科院分区：
文献类型：
--
作者：
Li Qian;Sun Xiwen;Tang Yunyi;Qu Yanan;Zhou Yanheng;Zhang Yu
尽管在空间和时间维度上普遍存在机械线索，但细胞身份和功能在很大程度上不受不断变化的机械刺激的影响。为了了解这种表观遗传稳定性的分子基础，我们研究了从人牙周膜 (PDLSC) 纯化的间充质干细胞中由压力引起的转录组变化，并分别鉴定了上调和弱下调基因中填充的 H3K27me3 和 E2F 特征。一致地，几个 E2F 家族转录因子和 EZH2（作为 H3K27me3 的核心甲基转移酶）的表达响应机械应力而降低，这归因于力诱导的 RB 从核质到核纤层的重新分配。重要的是，虽然对 H3K27me3 景观的表观基因组分析仅证明了一组机械反应基因的相关变化，但我们观察到超级增强子的全基因组不稳定以及异常的 EZH2 保留。这些超级增强子的一侧与 H3K27me3 结构域紧密结合，表现出 H3K27ac 沉积减弱、H3K27ac 峰变平以及受力暴露后 EZH2 表达得到补偿，类似于 H3K27ac 熵增加或 H3K27ac 极化减少。力诱导的 EZH2 还原的干扰可能会驱动 EZH2 和超级增强子之间依赖于肌动蛋白丝的空间重叠，并在功能上损害 PDLSC 在机械应力后的多能性。这些发现共同揭示了 EZH2 减少对于维持机械反应中的超级增强子稳定性和细胞特性的具体贡献。
Despite the ubiquitous mechanical cues at both spatial and temporal dimensions, cell identities and functions are largely immune to the everchanging mechanical stimuli. To understand the molecular basis of this epigenetic stability, we interrogated compressive force-elicited transcriptomic changes in mesenchymal stem cells purified from human periodontal ligament (PDLSCs), and identified H3K27me3 and E2F signatures populated within upregulated and weakly downregulated genes, respectively. Consistently, expressions of several E2F family transcription factors and EZH2, as core methyltransferase for H3K27me3, decreased in response to mechanical stress, which were attributed to force-induced redistribution of RB from nucleoplasm to lamina. Importantly, although epigenomic analysis on H3K27me3 landscape only demonstrated correlating changes at one group of mechanoresponsive genes, we observed a genome-wide destabilization of super-enhancers along with aberrant EZH2 retention. These super-enhancers were tightly bounded by H3K27me3 domain on one side and exhibited attenuating H3K27ac deposition and flattening H3K27ac peaks along with compensated EZH2 expression after force exposure, analogous to increased H3K27ac entropy or decreased H3K27ac polarization. Interference of force-induced EZH2 reduction could drive actin filaments dependent spatial overlap between EZH2 and super-enhancers and functionally compromise the multipotency of PDLSC following mechanical stress. These findings together unveil a specific contribution of EZH2 reduction for the maintenance of super-enhancer stability and cell identity in mechanoresponse.
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影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
DOI：
10.1083/jcb.201004067
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rodríguez J;Calvo F;González JM;Casar B;Andrés V;Crespo P
通讯作者：
Crespo P
影响因子：
46.9
作者：
Trapnell C;Williams BA;Pertea G;Mortazavi A;Kwan G;van Baren MJ;Salzberg SL;Wold BJ;Pachter L
通讯作者：
Pachter L
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.2741/1835
发表时间：
2006
期刊：
Frontiers in bioscience : a journal and virtual library
影响因子：
--
作者：
Y. Q. Yang;X. Li;A. Rabie;M. Fu;D. Zhang
通讯作者：
Y. Q. Yang;X. Li;A. Rabie;M. Fu;D. Zhang