ABSTRACT: Endometriosis is a benign yet invasive condition in which endometrial-like tissue grows outside the uterus. Recent evidence highlights the role of epigenetic mechanisms—particularly DNA methylation—in its development. DNA methyltransferases (DNMTs), including DNMT1, DNMT3B, and DNMT3A—regulate these modifications. DNMT3A is uniquely upregulated in the eutopic endometrium of women with endometriosis and may affect reproductive potential via altered gene expression. To investigate DNMT3A's role, we compared the incidence of endometriosis and transcriptomic profiles in Dnmt3a knockout (KO) mice and wild-type controls. RNA sequencing of KO samples revealed upregulation of pathways such as E2F_TARGETS, MYC_TARGETS_V1, G2M_CHECKPOINT, and UNFOLDED_PROTEIN_RESPONSE, and downregulation of NOTCH_SIGNALING, COAGULATION, HEDGEHOG_SIGNALING, ANGIOGENESIS, and ADIPOGENESIS. Several immune-related genes were also differentially expressed, including IL-6, CXCL1, CXCL2, IL-1β, TNFα, CCL5, CXCL5, TGFβ1, IL-10, CXCL9, CXCL10, CX3CL1, CCL2, CCL22, CCL17, and CXCL12. These findings suggest that elevated DNMT3A expression may contribute to immune suppression in endometriosis, and its loss leads to reactivation of immune response genes, highlighting DNMT3A as a potential therapeutic target.
