HDAC3 Regulates Transcriptional Networks Governing Decidualization

Decidualization is essential for embryo implantation and maintenance of pregnancy, during which quiescent endometrial stromal fibroblasts proliferate and differentiate into decidual stromal cells. Emerging evidence indicates that epigenetic regulators, including histone modifications, play critical roles in uterine receptivity, implantation, and stromal cell decidualization. Our previous study demonstrated that loss of histone deacetylase 3 (HDAC3) impairs endometrial receptivity and decidualization, resulting in female infertility. However, the genome-wide transcriptomic alterations responsible for defective decidualization in loss of HDAC3 remain unclear. In this study, uterine-specific Hdac3 knockout (Pgr^cre/+Hdac3^f/f; Hdac3^d/d) mice exhibited decidual defects following 3 days of artificial decidualization. RNA sequencing analysis of uteri from control and Hdac3^d/d mice revealed widespread dysregulation of genes and pathways associated with decidualization. Pathway analysis identified significant alterations in RHOA, AMPK-NOTCH1-HEY1, and oxidative stress-induced senescence signaling, implicating dysregulation of cytoskeletal remodeling, cellular metabolism, and oxidative stress responses in the HDAC3-mediated decidual response. Notably, expression of Limk1, Prkag1, and Cbx2 for key regulators of these pathways was significantly reduced in Hdac3^d/d mice compared with controls. These findings demonstrate that HDAC3 is a key regulator of the transcriptional and signaling networks required for successful decidualization. Collectively, our study provides a comprehensive transcriptomic profile of HDAC3-deficient uteri and uncovers key molecular mechanisms underlying impaired decidualization, thereby advancing our understanding of uterine function and pregnancy establishment.