HIF1A facilitates hypoxia-induced changes in H3K27ac modification to promote myometrial contractility.

Abstract

Prior studies have established that myometrial hypoxia during labor is pivotal in intensifying contractions, the alterations in gene expression and histone modifications in myometrial cells under hypoxia have yet to be documented. Here, hypoxia's enhancement of cellular contractility was confirmed, and RNA-seq identified 2,262 differentially expressed genes in human myometrial smooth muscle cells (hMSMCs) under hypoxia. Chromatin immunoprecipitation (ChIP), high-throughput chromosome conformation capture followed by ChIP (Hi-ChIP) were employed to investigate the epigenetic changes, specifically histone modifications (H3K27ac, H3K4me1, H3K27me3, and H3K4me3), in hMSMCs under hypoxia. We identified the enhancer and super-enhancer regions in hMSMCs and found HIF1A as the key mediator of these H3K27ac changes under hypoxia. Labor-associated genes regulated by HIF1A have been identified. Validation experiments on these genes such as CXCL8, RUNX1, IL-6, and PTGES3 demonstrated that HIF1A knockdown reduces their expression and associated H3K27ac modifications in peak regions of their promoters or enhancers. These findings indicate that HIF1A probably mediate changes in histone H3K27ac modifications to regulate myometrial cell contractions under hypoxia, providing potential therapeutic and intervention targets for disorders related to parturition.