TY - JOUR
T1 - Epigenetic histone methylation regulates transforming growth factor β-1 expression following bile duct ligation in rats
AU - Sheen-Chen, Shyr Ming
AU - Lin, Chung Ren
AU - Chen, Kuan Hung
AU - Yang, Chien Hui
AU - Lee, Chien Te
AU - Huang, Hui Wen
AU - Huang, Chun Ying
N1 - Funding Information:
This work was supported in part by grant No. 8A1011 and 880893 from Chang Gung Memorial Hospital Research, Kaohsiung, Taiwan, and by grant No. 101-2314-B-182-021, 100-2314-B-182-068, 101-2314-B-182-090, 101-2314-B-182A-014-, and 101-2314-B-182A-068-MY3 from the Taiwan National Science Council Research, Taipei, Taiwan.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
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U2 - 10.1007/s00535-013-0892-0
DO - 10.1007/s00535-013-0892-0
M3 - Article
C2 - 24097032
AN - SCOPUS:84905647959
SN - 0944-1174
VL - 49
SP - 1285
EP - 1297
JO - Journal of Gastroenterology
JF - Journal of Gastroenterology
IS - 8
ER -