Epigenetic histone methylation regulates transforming growth factor β-1 expression following bile duct ligation in rats

• Published in: Journal of gastroenterology 2014-08, Vol.49 (8), p.1285-1297
• Main Authors: Sheen-Chen, Shyr-Ming, Lin, Chung-Ren, Chen, Kuan-Hung, Yang, Chien-Hui, Lee, Chien-Te, Huang, Hui-Wen, Huang, Chun-Ying
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Animals; Bile Ducts - pathology; Biliary Tract; Chromatin Immunoprecipitation; Collagen; Colorectal Surgery; Epigenesis, Genetic; Gastroenterology; Gene Expression Regulation; Gene Knockdown Techniques; Hepatology; Histone-Lysine N-Methyltransferase - genetics; Histones - genetics; Histones - metabolism; Ligation; Liver Cirrhosis, Experimental - prevention & control; Male; Medicine; Medicine & Public Health; Methylation; Original Article—Liver; Pancreas; Rats; Rats, Sprague-Dawley; RNA, Small Interfering - administration & dosage; Surgical Oncology; Time Factors; Transforming Growth Factor beta1 - genetics
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-013-0892-0

Background Multiple mechanisms contribute to the liver fibrosis following cholestasis. Recent research has focused on the role of transforming growth factor β-1 (TGF-β1) in the progression of fibrosis. The aim of our study is to examine the role of epigenetic chromatin marks, such as histone H3 lysine methylation (H3Kme), in bile duct ligation (BDL)-induced TGF-β1 gene expression in rat liver. Methods Time course of methylated-histone H3 and SET7/9 recruitment were determined by chromatin immunoprecipitation in livers from BDL rats on days 1, 4, 9 and 14. Levels of TGF-β1 and SET7/9 were determined by western blots. The effect of SET7/9 knockdown on BDL-induced expression of TGF-β1, serum enzymes and liver collagen content was studied in vivo. Results Results showed that BDL increased the expression of the TGF β-1. Increased levels of active chromatin marks (H3K4me1, H3K4me2, and H3K4me3) and decreased levels of repressive marks (H3K9me2 and H3K9me3) in TGF-β1 promoter accompanied the changes in expression of the TGF β-1. BDL also increased expression of the H3K4 methyltransferase SET7/9 and recruitment to the promoter. SET7/9 gene knockdown with siRNAs significantly attenuated BDL-induced TGF-β1 gene expression, serum enzymes and liver collagen content. Conclusions Taken together, these results show the functional role of epigenetic chromatin histone H3Kme in BDL-induced TGF-β1 expression. Pharmacologic and other therapies that reverse these modifications could have potential hepatoprotective effects for BDL-induced cirrhosis.