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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

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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Abbreviations

α-SMA:

α-Smooth muscle actin

BDL:

Bile duct ligation

ChIP:

Chromatin immunoprecipitation

ECM:

Extracellular matrix

HATs:

Histone acetyl transferases

HDACs:

Histone deacetylases

HDMs:

Histone demethylases

HSC:

Hepatic stellate cell

H3KAc:

Acetylation of histone H3 lysines

H3Kme:

Histone H3 lysine methylation

qRT-PCR:

Quantitative reverse-transcription polymerase chain reaction

TB:

Total bilirubin

TGF-β1:

Transforming growth factor β-1

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Acknowledgments

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.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung, 833, Taiwan

    Shyr-Ming Sheen-Chen

  2. Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chung-Ren Lin, Kuan-Hung Chen, Chien-Hui Yang, Hui-Wen Huang & Chun-Ying Huang

  3. Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chien-Te Lee

  4. Department of Anesthesiology, National Taiwan University College of Medicine, Taipei, Taiwan

    Chung-Ren Lin

  5. Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Kuan-Hung Chen & Hui-Wen Huang

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  1. Shyr-Ming Sheen-Chen
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Correspondence to Chung-Ren Lin.

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Sheen-Chen, SM., Lin, CR., Chen, KH. et al. Epigenetic histone methylation regulates transforming growth factor β-1 expression following bile duct ligation in rats. J Gastroenterol 49, 1285–1297 (2014). https://doi.org/10.1007/s00535-013-0892-0

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