A Novel Role of the Sp/KLF Transcription Factor KLF11 in Arresting Progression of Endometriosis

Abstract

Endometriosis affects approximately 10% of young, reproductive-aged women. Disease associated pelvic pain; infertility and sexual dysfunction have a significant adverse clinical, social and financial impact. As precise disease etiology has remained elusive, current therapeutic strategies are empiric, unfocused and often unsatisfactory. Lack of a suitable genetic model has impaired further translational research in the field. In this study, we evaluated the role of the Sp/KLF transcription factor KLF11/Klf11 in the pathogenesis of endometriosis. KLF11, a human disease-associated gene is etiologically implicated in diabetes, uterine fibroids and cancer. We found that KLF11 expression was diminished in human endometriosis implants and further investigated its pathogenic role in Klf11-/- knockout mice with surgically induced endometriotic lesions. Lesions in Klf11-/- animals were large and associated with prolific fibrotic adhesions resembling advanced human disease in contrast to wildtype controls. To determine phenotype-specificity, endometriosis was also generated in Klf9-/- animals. Unlike in Klf11-/- mice, lesions in Klf9-/- animals were neither large, nor associated with a significant fibrotic response. KLF11 also bound to specific elements located in the promoter regions of key fibrosis-related genes from the Collagen, MMP and TGF-β families in endometrial stromal cells. KLF11 binding resulted in transcriptional repression of these genes. In summary, we identify a novel pathogenic role for KLF11 in preventing de novo disease-associated fibrosis in endometriosis. Our model validates in vivo the phenotypic consequences of dysregulated Klf11 signaling. Additionally, it provides a robust means not only for further detailed mechanistic investigation but also the ability to test any emergent translational ramifications thereof, so as to expand the scope and capability for treatment of endometriosis.

Krüppel-like factor 12 is a novel negative regulator of forkhead box O1 expression: a potential role in impaired decidualization

“…KLF12 belongs to the zinc finger-containing transcription factor family, which contains key mediators of endocrine/metabolic processes that play emerging key roles in human reproductive and uterine diseases [ 15 , 24 ]. For example, KLF11 is highly expressed in human urogenital tissues, and aberrant KLF11 expression has been linked to the pathogeneses of common uterine diseases, such as endometriosis and leiomyoma [ 25 , 26 ]. Moreover, loss of coregulation between KLF9 and PR may underlie the pathogenesis of endometriosis [ 27 ].…”

The estrogen–macrophage interplay in the homeostasis of the female reproductive tract

“…Macrophage phenotypic adaptations are mediated by specific transcription factors, such as Nuclear Factor-Kappa enhancer of activated B cells (NF-κB) that is crucial for the expression of genes linked to the M1 inflammatory response, and CCAAT-enhancer-binding protein-b (C/EBPb), Kruppel-like Factor-4 (KLF4) and the transcriptional repressor KLF11 involved in M2 gene expression (Bouhlel et al, 2007;Takeda et al, 2010;Lawrence and Natoli, 2011;Liao et al, 2011;Pello et al, 2012). Interestingly, some of these transcription factors are also highly expressed in the FRT and involved in reproductive tissue pathologies (Navarro et al, 2012;Daftary et al, 2013). Distinct phenotypes also correspond to specific adaptations of macrophage energy metabolism, so that resting and M2 macrophages produce energy by the potentiation of oxidative phosphorylation and tricarboxylic acid cycle, while M1 activation is associated with higher rates of glycolysis (Vats et al, 2006;Palsson-McDermott and O'Neill, 2013).…”

“…In vivo studies using artificially induced menstruation in mice recently allowed to demonstrate that inflammatory monocytes and monocyte-derived macrophages are recruited during the simultaneous phases of tissue breakdown and repair to perform phagocytosis of apoptotic endothelial cells and tissue debris along with resident macrophages (Cominelli et al, 2014;Cousins et al, 2016). Transcription factors linked to phenotypic activation in macrophages, such as members of the KLF family, are highly expressed in reproductive tissues and have also been involved in endometrial and FRT pathologies (Daftary et al, 2013;Simmen et al, 2015). deposition, under the influence of the local inflammatory and hormonal environment, while the reduction in tissue factor and thrombin levels creates a pro-hemorrhagic and fibrinolytic milieu that is associated with endometrial sloughing (Davies and Kadir, 2012).…”

The Krüppel-like factors in female reproductive system pathologies

“…KLF9, KLF11, KLF13) and surviving through adulthood, an ovarian phenotype characterized by dysfunctions in steroid hormone synthesis is not manifested throughout the reproductive years (Simmen et al ., 2004; Zeng et al ., 2007; Heard et al ., 2012; Daftary et al ., 2013). This finding is not congruent with the demonstrated regulation of several key steroidogenic genes transcript levels (LDLR, StAR and CYP11A) by KLF13 in ovarian granulosa cells (Natesampillai et al , 2008).…”