HBP1 enhances progesterone receptor activity and IGFBP1 expression driving endometrial decidualization

Decidualization of human endometrial stromal cells (HESCs) is one of the critical steps in the establishment of human pregnancy. Nevertheless, little is known about the molecular mechanisms underlying human decidualization. In this study, we identified high-mobility group box transcription factor 1 (HBP1) as a key player in the decidualization of HESCs. Knockdown of HBP1 expression significantly reduced the mRNA and protein expression levels of the decidualization markers insulin-like growth factor-binding protein 1 (IGFBP1) and forkhead box O1 (FOXO1). Although progesterone receptor (PGR) expression did not significantly change, the expression levels of PGR-regulated target molecules decreased. Furthermore, ChIP-Seq and RNA-Seq analyses revealed that HBP1 directly transcriptionally regulates IGFBP1 expression. Additionally, overexpression of HBP1 promoted the enrichment of histone H3K4me3 at the promoter regions of PGR and its target molecules FK506 binding protein 5 (FKBP5), Fos-related antigen 2 (FRA-2/FOSL2), and FK506-binding protein 4 (FKBP4), which indicated that HBP1 enhances PGR transcriptional activity. Clinical specimen analysis further confirmed that the expression of HBP1 and PGR target molecules was significantly downregulated in the endometria of patients with recurrent implantation failure. In conclusion, this study provides evidence that HBP1 plays an important regulatory role in embryo implantation.