Histone Deacetylase 3-Progesterone Receptor Cooperation Regulates Progesterone Responsiveness in the Uterus

Sohyeon Yun, Rong Li, Soo Lim Kim, Loan Thi Kim Nguyen, Shamsun Nahar, Keun Cheon Kim, Da-Hye Kang, DaHye Kang, Eunhee M Jeong, Lisa M Brennaman, Lisa Brennaman, Mistie P. Mills, Steven L. Young, Bruce A. Lessey, Tae Hoon Kim, Jung‐Yoon Yoo, Jung-Yoon Yoo, Jae‐Wook Jeong
MedComm · 2026 · vol. 7(11) , pp. e71122 · doi:10.1002/mco2.71122 · PMID:42996627 · PMC13740683 · W7225426642
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Abstract

Endometriosis affects a substantial proportion of women of reproductive age, with 30%-50% affected by infertility. A defining pathological feature is progesterone resistance resulting from impaired progesterone receptor (PGR) signaling, yet the underlying mechanisms remain incompletely understood. Here, we define conserved shared target genes of histone deacetylase 3 (HDAC3) and PGR in the mouse uterus using integrated transcriptomic and cistromic analyses, supported by uterine-specific Hdac3 and Pgr knockout mice. Co-immunoprecipitation and proximity ligation assays indicate that HDAC3 associates with PGR, with reciprocal attenuation of their expression in Hdac3- and Pgr-deficient uteri. Multiplex immunofluorescence demonstrates colocalization of HDAC3 and PGR in endometrial epithelial and stromal cells. HDAC3 and PGR expression levels show a positive correlation in stromal cells in both controls and infertile women with endometriosis, whereas this correlation in epithelial cells is selectively preserved in a subset of infertile cases. Chromatin profiling demonstrates extensive co-occupancy of HDAC3 and PGR at regulatory regions associated with progesterone-responsive genes. Together, these findings support a model in which HDAC3 functions as a coregulator of PGR-dependent transcription in the uterus and indicate that HDAC3-PGR cooperation is a key determinant of endometrial receptivity. This work provides mechanistic insight into progesterone resistance underlying endometriosis-associated infertility.

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