FHL1 mediates HOXA10 deacetylation via SIRT2 to enhance blastocyst-epithelial adhesion

Abstract

Recurrent implantation failure (RIF) is a rather thorny problem in the clinical practice of assisted reproductive technology. Due to the complex aetiology of RIF, its pathogenesis is far from fully understood, and there is no effective treatment available. Here, We explored the regulatory mechanism of the four half-domains of LIM domain 1 (FHL1), which is significantly downregulated in the endometrium of RIF patients, in blastocyst-epithelial adhesion. Indeed, FHL1 expression was dramatically increased in normal female mid-secretory endometrial epithelial cells and was abnormally reduced in RIF patients. Furthermore, FHL1 overexpression promoted blastocyst-epithelial adhesion, and interfering with FHL1 expression in the mouse uterus significantly inhibited embryo implantation. Mechanistically, FHL1 did not regulate HOXA10 mRNA expression but increased HOXA10 protein stability and activated HOXA10, thereby promoting its regulation of downstream gene expression and the β3 integrin/FAK pathway. Meanwhile, FHL1 regulates HOXA10 function by increasing HOXA10 deacetylation through enhanced binding of HOXA10 and SIRT2. SIRT2-specific inhibitors can significantly inhibit this effect. In the endometrial epithelial cells of RIF patients, the correlation between FHL1 and HOXA10 and its downstream target genes has also been verified. Finally, our data indicated FHL1 is a regulatory molecule that promotes blastocyst-epithelial adhesion. Altogether, downstream dysfunction due to aberrant FHL1 expression is an important molecular basis for embryo implantation failure in patients with RIF and to provide new potential therapeutic targets.

Proteomic Analysis of Domestic Cat Blastocysts and Their Secretome Produced in an In Vitro Culture System without the Presence of the Zona Pellucida

“…Furthermore, in mice, KRT86 is upregulated in the uterus during implantation, which indicates that this keratin might be involved in embryo implantation [99]. Other proteins important for cell adhesion and embryo implantation were identified in ZI blastocysts: desmoplakin, plakophilin 1, annexin A2 and FHL1 [100,115,146,147].…”

Distinct subtypes of endometriosis identified based on stromal-immune microenvironment and gene expression: implications for hormone therapy

“…FHL1, a member of the four-and-a-half-LIM-only protein family, might be involved in muscle development or hypertrophy. Another study showed that FHL1 promotes blastocyst-epithelial adhesion ( 31 ). Therefore, we speculated that FHL1 might mediate the excessive adhesion of endometrial epithelial cells to the ectopic milieu, which is the opposite role.…”