TET3 inhibits the decidualization of human endometrial stromal cells by regulating ITGA10 transcription through recruiting HDAC1/2.

Decidualization is a critical physiological process necessary for successful embryo implantation and pregnancy maintenance. Disruptions in this process can result in infertility and various pregnancy complications. Ten-eleven translocation protein 3 (TET3) is a key molecule in the dedifferentiation process, but its pathogenic mechanism remains unclear. In this study, we aimed to uncover the molecular mechanisms by which TET3 modulates decidualization through utilizing an in vitro ESC model overexpressing TET3. TET3 overexpression was found to inhibit the transcription of ITGA10 (integrin subunit alpha 10), a novel downstream target, thereby suppressing the proliferation and migration of endometrial stromal cells. This repression of ITGA10 is independent of TET3's catalytic activity and instead relies on its non-catalytic function. Mechanistically, TET3 recruits histone deacetylases 1 and 2 (HDAC1/2) to the ITGA10 promoter to repress its transcription. Silencing HDAC1 or HDAC2 individually had little effect on the repressive action of TET3. However, simultaneous knockdown of HDAC1 and HDAC2 via siRNA, or pharmacological inhibition using the HDAC1/2 inhibitor romidepsin, effectively reversed TET3-mediated repression of ITGA10. These findings uncover a non-catalytic role for TET3 in regulating decidualization and provide insights into potential therapeutic targets for pregnancy-related disorders.