(128) Progesterone Receptor Cooperates with HDAC3 to Establish Endometrial Receptivity

Sohyeon Yun¹, Soo Lim Kim¹, Rong Li ¹, Loan Thi Kim Nguyen¹, Shamsun Nahar¹, Keun Cheon Kim¹, DaHye Kang¹, Eunhee M. Jeong¹, Steven L. Young², Bruce A. Lessey³, Jung-Yoon Yoo⁴, Tae Hoon Kim¹, and Jae-Wook Jeong¹

¹Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO, USA

²Department of Obstetrics, Gynecology and Women's Health, Duke University, Durham, NC, USA

³Department of Obstetrics and Gynecology, Wake Forest Baptist Health, Winston-Salem, NC, USA

⁴Department of Biomedical Laboratory Science, Yonsei University Mirae Campus, Wonju, Republic of Korea

Abstract Text:

Endometriosis is prevalent among women at reproductive age, with 30-50% experiencing infertility. Progesterone resistance is a known pathologic condition in endometriosis caused by aberrant progesterone signaling, however, its underlying mechanisms remain unclear. In this study, we identified highly conserved target genes of histone deacetylase 3 (HDAC3) and progesterone receptor (PGR) in the mouse uterus using integrated transcriptomic and ChIP-seq analyses, as well as knockout models of Hdac3 and Pgr.  Our immunoprecipitation assay revealed a protein-protein interaction between HDAC3 and PGR. Furthermore, PRKO and Hdac3-knockout mice exhibited a significant attenuation of HDAC3 and PGR expression in the uterus, respectively. To determine the colocalization and correlation of HDAC3 and PGR in endometrial epithelial and stromal cells, we performed multiplex immunofluorescence. Importantly, their expression levels showed a significant positive correlation in stromal cells in both the control and infertile women with endometriosis group. However, in epithelial cells, this correlation was observed only in the infertile endometriosis group. This finding demonstrates the cooperative interactions of HDAC3 and PGR in nuclear hormone receptor-dependent epigenetic regulation. Our study enhances the understanding of progesterone resistance in endometriosis-related infertility and reveals PGR/HDAC3 interactions as critical regulator of endometrial receptivity. This work was supported by NIH R01HD101243, and R01HD102170.