Abstract |
Transforming growth factor (TGF-β) induced activation of portal fibroblast cells serves as a primary cause for liver fibrosis following cholestatic injury. The underlying epigenetic mechanism is not clear. We studied the role of a transcriptional modulator, megakaryoblastic leukemia 1 (MKL1) in this process. We report here that MKL1 deficiency ameliorated BDL-induced liver fibrosis in mice as assessed by histological stainings and expression levels of pro-fibrogenic genes. MKL1 silencing by small interfering RNA ( siRNA) abrogated TGF-β induced transactivation of pro-fibrogenic genes in portal fibroblast cells. TGF-β stimulated the binding of MKL1 on the promoters of pro-fibrogenic genes and promoted the interaction between MKL1 and SMAD3. While SMAD3 was necessary for MKL1 occupancy on the gene promoters, MKL1 depletion impaired SMAD3 binding reciprocally. TGF-β treatment induced the accumulation of trimethylated histone H3K4 on the gene promoters by recruiting a methyltransferase complex. Knockdown of individual members of this complex significantly weakened the binding of SMAD3 and down-regulated the activation of portal fibroblast cells. In conclusion, we have identified an epigenetic pathway that dictates TGF-β induced pro-fibrogenic transcription in portal fibroblast thereby providing novel insights for the development of therapeutic solutions to treat liver fibrosis.
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Authors | Zhiwen Fan, Chenzhi Hao, Min Li, Xin Dai, Hao Qin, Jianfei Li, Huihui Xu, Xiaoyan Wu, Liping Zhang, Mingming Fang, Bisheng Zhou, Wenfang Tian, Yong Xu |
Journal | Biochimica et biophysica acta
(Biochim Biophys Acta)
Vol. 1849
Issue 9
Pg. 1219-28
(Sep 2015)
ISSN: 0006-3002 [Print] Netherlands |
PMID | 26241940
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier B.V. All rights reserved. |
Chemical References |
- Smad3 Protein
- Smad3 protein, mouse
- Transforming Growth Factor beta
- MAP Kinase Kinase Kinases
- Map3k9 protein, mouse
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Topics |
- Animals
- Bile Ducts
(surgery)
- Cells, Cultured
- Epigenesis, Genetic
- Liver Cirrhosis
(physiopathology)
- MAP Kinase Kinase Kinases
(metabolism, physiology)
- Male
- Mice
- Mice, Knockout
- Protein Binding
- Rats
- Smad3 Protein
(metabolism)
- Transforming Growth Factor beta
(physiology)
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