title: Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis.
abstract: Progressive fibrosis is recalcitrant to conventional therapy and commonly complicates chronic diseases and surgical healing. We evaluate here a novel mechanism that regulates scar-tissue collagen (COL1A1/Col1a1) expression and characterizes its translational relevance as a targeted therapy for fibrosis in an endometriosis disease model. Endometriosis is caused by displacement and implantation of uterine endometrium onto abdominal organs and spreads with progressive scarring. Transcription factor KLF11 is specifically diminished in endometriosis lesions. Loss of KLF11-mediated repression of COL1A1/Col1a1 expression resulted in increased fibrosis. To determine the biological significance of COL1A1/Col1a1 expression on fibrosis, we modulated its expression. In human endometrial-stromal fibroblasts, KLF11 recruited SIN3A/HDAC (histone deacetylase), resulting in COL1A1-promoter deacetylation and repression. This role of KLF11 was pharmacologically replicated by a histone acetyl transferase inhibitor (garcinol). In contrast, opposite effects were obtained with a HDAC inhibitor (suberoyl anilide hydroxamic acid), confirming regulatory specificity for these reciprocally active epigenetic mechanisms. Fibrosis was concordantly reversed in Klf11(-/-)animals by histone acetyl transferase inhibitor and in wild-type animals by HDAC inhibitor treatments. Aberrant lesional COL1A1 regulation is significant because fibrosis depended on lesion rather than host genotype. This is the first report demonstrating feasibility for targeted pharmacological reversal of fibrosis, an intractable phenotype of diverse chronic diseases.
authors.affiliation: Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Zaraq
authors.initials: Z
authors.lastname: Khan
authors.affiliation: Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zanfagnin
authors.affiliation: Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Correa
authors.affiliation: Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Abigail A
authors.initials: AA
authors.lastname: Delaney
authors.affiliation: Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota daftary.gaurang@mayo.edu.
authors.forename: Gaurang S
authors.initials: GS
authors.lastname: Daftary
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D005355:Fibrosis; D005838:Genotype; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D024042:Collagen Type I; C115117:KLF11 protein, human; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: collagen 1; endometriosis; epigenetic modulators; fibrosis; gene transcription