MeCP2 Controls an Epigenetic Pathway That Promotes Myofibroblast Transdifferentiation and Fibrosis

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2009 Oct 22

PMID 19843474

Citations 193

Authors

Jelena Mann

David C K Chu

Aidan Maxwell

Fiona Oakley

Nian-Ling Zhu

Hidekazu Tsukamoto

Derek A Mann

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Myofibroblast transdifferentiation generates hepatic myofibroblasts, which promote liver fibrogenesis. The peroxisome proliferator-activated receptor gamma (PPARgamma) is a negative regulator of this process. We investigated epigenetic regulation of PPARgamma and myofibroblast transdifferentiation.

Methods: Chromatin immunoprecipitation (ChIP) assays assessed the binding of methyl-CpG binding protein 2 (MeCP2) to PPARgamma and chromatin modifications that silence this gene. MeCP2(-/y) mice and an inhibitor (DZNep) of the epigenetic regulatory protein EZH2 were used in the carbon tetrachloride model of liver fibrosis. Liver tissues from mice were assessed by histologic analysis; markers of fibrosis were measured by quantitative polymerase chain reaction (qPCR). Reverse transcription PCR detected changes in expression of the microRNA miR132 and its target, elongated transcripts of MeCP2. Myofibroblasts were transfected with miR132; PPARgamma and MeCP2 expressions were analyzed by qPCR or immunoblotting.

Results: Myofibroblast transdifferentiation of hepatic stellate cells is controlled by a combination of MeCP2, EZH2, and miR132 in a relay pathway. The pathway is activated by down-regulation of miR132, releasing the translational block on MeCP2. MeCP2 is recruited to the 5' end of PPARgamma, where it promotes methylation by H3K9 and recruits the transcription repressor HP1alpha. MeCP2 also stimulates expression of EZH2 and methylation of H3K27 to form a repressive chromatin structure in the 3' exons of PPARgamma. Genetic and pharmacologic disruptions of MeCP2 or EZH2 reduced the fibrogenic characteristics of myofibroblasts and attenuated fibrogenesis.

Conclusions: Liver fibrosis is regulated by an epigenetic relay pathway that includes MeCP2, EZH2, and miR132. Reagents that interfere with this pathway might be developed to reduce fibrogenesis in chronic liver disease.

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References

Chahrour M, Jung S, Shaw C, Zhou X, Wong S, Qin J . MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008; 320(5880):1224-9. PMC: 2443785. DOI: 10.1126/science.1153252. View

Fuks F, Hurd P, Deplus R, Kouzarides T . The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003; 31(9):2305-12. PMC: 154218. DOI: 10.1093/nar/gkg332. View

Oakley F, Mann J, Nailard S, Smart D, Mungalsingh N, Constandinou C . Nuclear factor-kappaB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. Am J Pathol. 2005; 166(3):695-708. PMC: 1602348. DOI: 10.1016/s0002-9440(10)62291-2. View

Wynn T . Cellular and molecular mechanisms of fibrosis. J Pathol. 2007; 214(2):199-210. PMC: 2693329. DOI: 10.1002/path.2277. View

Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee P . Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007; 21(9):1050-63. PMC: 1855231. DOI: 10.1101/gad.1524107. View

Wright M, Issa R, Smart D, Trim N, Murray G, Primrose J . Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology. 2001; 121(3):685-98. DOI: 10.1053/gast.2001.27188. View

Cao R, Zhang Y . The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004; 14(2):155-64. DOI: 10.1016/j.gde.2004.02.001. View

Aiello A, Pandini G, Frasca F, Conte E, Murabito A, Sacco A . Peroxisomal proliferator-activated receptor-gamma agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells. Endocrinology. 2006; 147(9):4463-75. DOI: 10.1210/en.2005-1610. View

Iredale J . Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007; 117(3):539-48. PMC: 1804370. DOI: 10.1172/JCI30542. View

10.

Kirmizis A, Bartley S, Kuzmichev A, Margueron R, Reinberg D, Green R . Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004; 18(13):1592-605. PMC: 443521. DOI: 10.1101/gad.1200204. View

11.

Saika S, Yamanaka O, Okada Y, Miyamoto T, Kitano A, Flanders K . Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice. Am J Physiol Cell Physiol. 2007; 293(1):C75-86. DOI: 10.1152/ajpcell.00332.2006. View

12.

Helbling Chadwick L, Wade P . MeCP2 in Rett syndrome: transcriptional repressor or chromatin architectural protein?. Curr Opin Genet Dev. 2007; 17(2):121-5. DOI: 10.1016/j.gde.2007.02.003. View

13.

Milam J, Keshamouni V, Phan S, Hu B, Gangireddy S, Hogaboam C . PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2007; 294(5):L891-901. PMC: 5926773. DOI: 10.1152/ajplung.00333.2007. View

14.

Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne A, Mann D . Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ. 2006; 14(2):275-85. DOI: 10.1038/sj.cdd.4401979. View

15.

Hite K, Adams V, Hansen J . Recent advances in MeCP2 structure and function. Biochem Cell Biol. 2009; 87(1):219-27. PMC: 2874317. DOI: 10.1139/O08-115. View

16.

Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F . RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature. 2006; 441(7092):469-74. DOI: 10.1038/nature04674. View

17.

Schwartz Y, Pirrotta V . Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet. 2006; 8(1):9-22. DOI: 10.1038/nrg1981. View

18.

Yang L, Chan C, Kwon O, Liu S, McGhee J, Stimpson S . Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2006; 291(5):G902-11. DOI: 10.1152/ajpgi.00124.2006. View

19.

Goldberg A, Allis C, Bernstein E . Epigenetics: a landscape takes shape. Cell. 2007; 128(4):635-8. DOI: 10.1016/j.cell.2007.02.006. View

20.

Klein M, Lioy D, Ma L, Impey S, Mandel G, Goodman R . Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci. 2007; 10(12):1513-4. DOI: 10.1038/nn2010. View