KLFII 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.

p38 Mitogen-Activated Protein Kinase is Involved in the Pathogenesis of Endometriosis by Modulating Inflammation, but not Cell Survival

“…60,65 However, further studies are required to investigate the role of p38 MAPK in other endometriosisrelated cellular mechanisms, such as reactive oxygen species-induced impaired immune response 1 and/or epithelialmesenchymal transition that induce fibrotic tissue formation, which Zheng et al have recently demonstrated to be a hallmark of deep infiltrating endometriotic lesions. 66,67 Due to restrictions in isolation and growing pure culture of endometrial epithelial cells as well as their limitation in passaging in culture, especially from ectopic sites, has prevented us in performing in vitro comparisons of the role p38 MPAK signaling in regulating proliferation, apoptosis, and cytokine secretion in normal versus endometriotic epithelial cells. Another limitation of the study was that the information about stage and severity of endometriosis was not available in some cases and, therefore, stage and severity of endometriosis were not reported in this study.…”

“…60,65 However, further studies are required to investigate the role of p38 MAPK in other endometriosis-related cellular mechanisms, such as reactive oxygen species–induced impaired immune response 1 and/or epithelial–mesenchymal transition that induce fibrotic tissue formation, which Zheng et al have recently demonstrated to be a hallmark of deep infiltrating endometriotic lesions. 66,67…”

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

“…On the other hand, genetic deletion of KLF11 aggravates ischemic brain injury [ 30 ]. KLF11 KO mice were associated with progressive fibrosis in a murine model of endometriosis [ 31 ]. KLF11 is decreased in endometriosis lesions.…”

Novel TRERF1 mutations in Chinese patients with ovarian endometriosis

“…It is characterized by chronic pelvic pain and subfertility or infertility, and affects the quality life of the affected individuals (3)(4)(5). Despite the progress made in elucidating the molecular etiology of endometriosis, due to heterogeneity of this disorder, there are individuals with unknown molecular/genetic alterations which are affected by endometriosis (6)(7)(8)(9).…”