Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis1

Ye Zheng, Zaraq Khan, Valentina Zanfagnin, Luiz F Correa, Abigail A Delaney, Gaurang S Daftary
Biology of reproduction · 2016 · vol. 94(4) , pp. 87 · doi:10.1095/biolreprod.115.138115 · PMID:26935598 · W2294542452
article OA: closed CC0 ⤵ 30 in-corpus citations
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This study shows that diminished KLF11 transcription factor increases COL1A1 expression and fibrosis in endometriosis, and this process can be reversed by epigenetic modulation with histone acetyltransferase or histone deacetylase inhibitors.

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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.

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Condition tags

endometriosis

MeSH descriptors

Cell Cycle Proteins Collagen Type I Endometriosis Epigenesis, Genetic Repressor Proteins Animals Apoptosis Regulatory Proteins Cell Cycle Proteins Collagen Type I Collagen Type I Disease Models, Animal Disease Progression Endometriosis Endometriosis Endometriosis Female Fibrosis Genotype Histone Deacetylases Histone Deacetylases

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