| First Author | Fan Z | Year | 2015 |
| Journal | Biochim Biophys Acta | Volume | 1849 |
| Issue | 9 | Pages | 1219-28 |
| PubMed ID | 26241940 | Mgi Jnum | J:231353 |
| Mgi Id | MGI:5770221 | Doi | 10.1016/j.bbagrm.2015.07.013 |
| Citation | Fan Z, et al. (2015) MKL1 is an epigenetic modulator of TGF-beta induced fibrogenesis. Biochim Biophys Acta 1849(9):1219-28 |
| abstractText | Transforming growth factor (TGF-beta) 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-beta induced transactivation of pro-fibrogenic genes in portal fibroblast cells. TGF-beta 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-beta 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-beta induced pro-fibrogenic transcription in portal fibroblast thereby providing novel insights for the development of therapeutic solutions to treat liver fibrosis. |
