KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis

Abstract

Endometriosis is a highly prevalent, chronic, heterogeneous, fibro-inflammatory disease that remains recalcitrant to conventional therapy. We previously showed that loss of KLF11, a transcription factor implicated in uterine disease, results in progression of endometriosis. Despite extensive homology, co-expression, and human disease association, loss of the paralog Klf10 causes a unique inflammatory, cystic endometriosis phenotype in contrast to fibrotic progression seen with loss of Klf11. We identify here for the first time a novel role for KLF10 in endometriosis. In an animal endometriosis model, unlike wild-type controls, Klf10−/− animals developed cystic lesions with massive immune infiltrate and minimal peri-lesional fibrosis. The Klf10−/− disease progression phenotype also contrasted with prolific fibrosis and minimal immune cell infiltration seen in Klf11−/− animals. We further found that lesion genotype rather than that of the host determined each unique disease progression phenotype. Mechanistically, KLF10 regulated CD40/CD154-mediated immune pathways. Both inflammatory as well as fibrotic phenotypes are the commonest clinical manifestations in chronic fibro-inflammatory diseases such as endometriosis. The complementary, paralogous Klf10 and Klf11 models therefore offer novel insights into the mechanisms of inflammation and fibrosis in a disease-relevant context. Our data suggests that divergence in underlying gene dysregulation critically determines disease-phenotype predominance rather than the conventional paradigm of inflammation being precedent to fibrotic scarring. Heterogeneity in clinical progression and treatment response are thus likely from disparate gene regulation profiles. Characterization of disease phenotype-associated gene dysregulation offers novel approaches for developing targeted, individualized therapy for recurrent and recalcitrant chronic disease.

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

“…Moreover, consistent with the view that fibrogenesis entails epigenetic aberrations, 410 growing evidence indicates that in endometriosis fibrogenesis also involves epigenetic changes. 61,71,411,412 This raises the question as whether hormonal therapeutics can actually modify the epigenetic aberration, resulting in a gradual reverse of fibrogenesis, especially in highly fibrotic lesions such as DE. A recent study reports that, dienogest, a synthetic progestin, is effective in alleviating symptoms but does not reduce nodular size in DE, 413 suggesting that hormonal therapeutics cannot modify the epigenetic aberration that is already in place.…”

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

“…28 Upon activation (phosphorylation), p38 MAPK induces phosphorylation of its substrates at serine and/or threonine residues 29 to activate downstream molecules such as translation/transcription factors, cell cycle molecules, kinases, or scaffold proteins, resulting in a variety of cellular outputs, including cytokine production, proliferation, cycle arrest, migration, differentiation, and apoptosis. [30][31][32][33] Previously, we showed that E 2 induces p38 MAPK phosphorylation (activation) in endometrial stromal cells (ESCs) within minutes, 34 suggesting that local E 2 production in endometriosis may cause constant p38 MAPK activation. Moreover, enhanced secretion of pro-inflammatory cytokines by immune cells in an ectopic site may further increase p38 MAPK activation in endometriosis implants in a paracrine manner.…”

“…28 Upon activation (phosphorylation), p38 MAPK induces phosphorylation of its substrates at serine and/or threonine residues 29 to activate downstream molecules such as translation/transcription factors, cell cycle molecules, kinases, or scaffold proteins, resulting in a variety of cellular outputs, including cytokine production, proliferation, cycle arrest, migration, differentiation, and apoptosis. 30 –33…”

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

“…10 Loss of KLF-mediated expression results in epigenetic dysregulation of target gene transcription and expression, resulting in the progression of endometriosis. 5,14,26 To determine whether loss of KLF11 in primary endometriotic epithelial cells altered DRD2 expression, we transfected 12Z cells with KLF11siRNA and compared DRD2 mRNA expression against scrambled control-transfected cells at 24, 48, and 72 hours (Figure 3A). As in Ishikawa cells, diminished KLF11 expression repressed DRD2 mRNA expression at least 2-fold compared to controls.…”