Zheng Ye, Khan Zaraq, Zanfagnin Valentina, Correa Luiz F, Delaney Abigail A, Daftary Gaurang S
Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
Laboratory of Translation Epigenetics in Reproduction, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota
Biol Reprod. 2016 Apr;94(4):87. doi: 10.1095/biolreprod.115.138115. Epub 2016 Mar 2.
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.
进行性纤维化对传统疗法具有抗性，并且通常会使慢性疾病和手术愈合复杂化。我们在此评估一种调节瘢痕组织胶原蛋白（COL1A1/Col1a1）表达的新机制，并将其作为子宫内膜异位症疾病模型中纤维化靶向治疗的转化相关性进行表征。子宫内膜异位症是由子宫内膜移位并植入腹部器官引起的，并随着瘢痕的进展而扩散。转录因子KLF11在子宫内膜异位症病变中特异性降低。KLF11介导的对COL1A1/Col1a1表达的抑制作用丧失导致纤维化增加。为了确定COL1A1/Col1a1表达对纤维化的生物学意义，我们调节了其表达。在人子宫内膜基质成纤维细胞中，KLF11募集SIN3A/HDAC（组蛋白去乙酰化酶），导致COL1A1启动子去乙酰化和抑制。KLF11的这一作用可通过组蛋白乙酰转移酶抑制剂（藤黄菌素）在药理学上得以重现。相反，使用HDAC抑制剂（辛二酰苯胺异羟肟酸）可获得相反的效果，证实了这些相互作用的表观遗传机制的调节特异性。组蛋白乙酰转移酶抑制剂可使Klf11(-/-)动物的纤维化得到一致逆转，HDAC抑制剂处理可使野生型动物的纤维化得到逆转。异常的病变COL1A1调节具有重要意义，因为纤维化取决于病变而非宿主基因型。这是第一份证明针对纤维化进行靶向药理逆转可行性的报告，纤维化是多种慢性疾病难以治疗的表型。
