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EZH2 reduction is an essential mechanoresponse for the maintenance of super-enhancer polarization against compressive stress in human periodontal ligament stem cells.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-09-15 , DOI: 10.1038/s41419-020-02963-3
Qian Li 1 , Xiwen Sun 2 , Yunyi Tang 2 , Yanan Qu 2 , Yanheng Zhou 1 , Yu Zhang 2
Affiliation  

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.



中文翻译:

EZH2 减少是维持人牙周膜干细胞中抗压应力的超增强子极化的基本机械反应。

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) 中纯化的间充质干细胞中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的 H3K27me3 和 E2F 特征。一致地,作为 H3K27me3 的核心甲基转移酶的几个 E2F 家族转录因子和 EZH2 的表达在响应机械应力时降低,这归因于力诱导的 RB 从核质重新分布到椎板。重要的,尽管对 H3K27me3 景观的表观基因组分析仅证明了一组机械响应基因的相关变化,但我们观察到超增强子的全基因组不稳定以及异常的 EZH2 保留。这些超级增强剂在一侧与 H3K27me3 结构域紧密结合,并表现出 H3K27ac 沉积减弱和 H3K27ac 峰变平以及受力暴露后 EZH2 表达的补偿,类似于 H3K27ac 熵增加或 H3K27ac 极化降低。力诱导的 EZH2 减少的干扰可以驱动肌动蛋白丝依赖 EZH2 和超级增强剂之间的空间重叠,并在功能上损害 PDLSC 在机械应力后的多能性。

更新日期:2020-09-16
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