KLF11 is an Epigenetic Mediator of DRD2/Dopaminergic Signaling in Endometriosis

Abstract

Endometriosis is a heterogeneous, recalcitrant disease that affects 10% of reproductive-age women. Resistance to conventional therapy critically raises the need for novel treatment options that target specific, dysregulated underlying molecular mechanisms. Dopamine receptor 2 (DRD2) has been shown to be associated with vascularity and fibrosis in endometriosis. Transcription factor KLF11 has been implicated in the pathogenesis of several human endocrine and reproductive tract diseases including endometriosis. KLF11 recruits epigenetic cofactors for regulation of target genes; dysregulation of critical target genes and associated signaling pathways results in diverse disease phenotypes. KLF11 regulates the expression of DRD2 in neurons. We investigated the regulation of DRD2 by KLF11 in the established eutopic and ectopic endometrial cell lines as well as in an animal model of endometriosis. KLF11 binding and activation of the DRD2 promoter was conserved across species. Promoter activation was reflected in correspondingly increased gene expression in an endometrial cell line and in primary endometriotic cells. In vivo, disease relevance was further evaluated in a surgically induced murine endometriotic model using Klf11−/− and wild-type mice. Consistent with loss of Klf11-mediated activation, lesions in Klf11−/− animals were associated with progressive fibrosis and decreased Drd2 expression. KLF11 binds specific epigenetic corepressors to repress several target genes. Activation of DRD2 by KLF11 could not be explained simply by loss of corepressor binding and is thus likely due to selective coactivator recruitment; identification of the precise pathway is the focus of ongoing investigation. Characterization of pharmacologically reversible epigenetic regulatory mechanisms has translational relevance in health and disease.