title: 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.
authors.affiliation: Laboratory of Translational Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA. daftary.gaurang@mayo.edu
authors.forename: Gaurang S
authors.initials: GS
authors.lastname: Daftary
authors.forename: Ye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zaid M
authors.initials: ZM
authors.lastname: Tabbaa
authors.forename: John K
authors.initials: JK
authors.lastname: Schoolmeester
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Gada
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Grzenda
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Mathison
authors.forename: Gary L
authors.initials: GL
authors.lastname: Keeney
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D003094:Collagen / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004717:Endometrium / Q000166:cytology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins; D017154:Stromal Cells / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C506460:KLF11 protein, mouse; C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D003094:Collagen; D020782:Matrix Metalloproteinases
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