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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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The apoptosis that occurs in the immature testis under physiological conditions is necessary for male germ cell development, whereas improper activation of apoptosis can impair spermatogenesis and cause defects in reproduction. We previously demonstrated that in mice, the makorin-2 ( Mkrn2 ) gene is expressed exclusively in the testis and its deletion leads to male infertility. To understand the potential molecular mechanism, in this study, we found that levels of apoptosis in the testis were abnormally high in the absence of Mkrn2 . To identify specific gene(s) involved, we performed digital gene expression profiling (DGE) and pathway analysis via gene set enrichment analysis (GSEA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and we found that MKRN2 inhibits p53 apoptosis effector related to PMP22 (PERP) expression and that levels of the protein in sperm samples have an inverse correlation with infertility levels. GSEA additionally indicated that PERP is a negative regulator of spermatogenesis and that its ectopic expression induces male infertility. Further, Gene Expression Omnibus (GEO) dataset analysis showed that p53, upstream of PERP, was upregulated in oligoasthenoteratozoospermia (OAT). These observations suggest that Mkrn2 is crucial for protecting germ cells from excessive apoptosis and implicate Mkrn2 -based suppression of the p53/PERP signaling pathway in spermatogenesis and male fertility.