BAZ2B contributes to endometrial fibrosis by promoting fibroblast-to-myofibroblast differentiation.

Endometrial fibrosis is a repair process of the endometrium that is commonly associated with trauma to the endometrium from surgical procedures, primarily curettage, and these dysfunctions lead to embryo implantation dysfunction and consequent infertility or spontaneous abortion. However, the underlying molecular mechanisms and genetic determinants driving endometrial fibrosis are largely unknown. Here, we conducted a systematic drug screen using an epigenetic compound library to investigate the epigenetic mechanism essential for endometrial fibrosis, and identified an epigenetic reader, bromodomain adjacent to zinc finger 2B (BAZ2B), from the bromodomain family, as a novel regulator of endometrial fibrosis. We found that BAZ2B knockdown or Baz2-specific inhibitor GSK2801 significantly attenuated TGFβ1-induced myofibroblast activation and extracellular matrix (ECM) production, while BAZ2B overexpression promoted these effects. Further, transcriptomic assay showed that BAZ2B knockdown reduced the expression of myofibroblast activation-related genes. The combination analysis of RNA-seq and CUT&Tag-seq assays uncovered that BAZ2B knockdown reduced the enrichment of H3K4me3 on the promoter of myofibroblast activation-associated genes, leading to down-regulation of ECM-related genes in myofibroblasts. More importantly, in a mouse intrauterine adhesions model, using GSK2801 treatment promoted endometrial regeneration and attenuated collagen deposition after mechanical injury. Collectively, these findings reveal a central role of BAZ2B in endometrial fibrosis and imply that BAZ2B is a potential therapeutic target to treat endometrial fibrotic disease.