TCF21 promotes epithelial-to-mesenchymal transition and cytoskeleton reorganization in uterine development and endometriosis.

Abstract

Endometriosis is a common gynecological disease associated with pelvic pain and infertility. Despite several existing theories, the etiology and molecular mechanisms of endometriosis remain to be investigated. Here we report that transcription factor 21 (TCF21) regulates uterine development and endometriosis pathogenesis by promoting epithelial-to-mesenchymal transition (EMT) and cytoskeleton reorganization. Uterine-specific knockout of Tcf21 in mice promotes EMT of the endometrium and dysplasia of the uterus. Accordingly, patients with endometriosis exhibit high TCF21 expression and an expanded population of stromal cells in both eutopic and ectopic endometria. Integrative epigenomic and transcriptomic analyses in patient-derived ectopic stromal cells reveal that TCF21 transcriptionally activated a cohort of genes, including LIMK2, which is critically involved in cytoskeleton organization. Indeed, TCF21-activated LIMK2-cofilin signaling in stromal cells is associated with actin-cytoskeleton reorganization and increased cell invasion and adhesion. In a surgically constructed mouse model, depletion of Tcf21 in eutopic stromal cells alleviates endometriotic lesions, whereas treatment of mice with AAV-Pgr-Tcf21 leads to increased endometriosis incidence, which could be mitigated by administering the LIM kinase inhibitor LIMKi 3. These observations uncover the importance of the TCF21-LIMK2-cofilin axis in uterine development and endometriosis, supporting the pursuit of TCF21-LIMK2-cofilin targeting in the diagnosis and therapeutics of endometriosis.