Gastroenterology
Volume 138, Issue 2 , Pages 705-714.e4 , February 2010

MeCP2 Controls an Epigenetic Pathway That Promotes Myofibroblast Transdifferentiation and Fibrosis

  • Jelena Mann

      Affiliations

    • Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    • Corresponding Author InformationReprint requests Address requests for reprints to: Jelena Mann, Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, Cookson Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE24HH, United Kingdom. fax: (44) 191 222 5455
    • ,
  • David C.K. Chu

      Affiliations

    • The University of Georgia College of Pharmacy, Athens, GA
    • ,
  • Aidan Maxwell

      Affiliations

    • Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    • ,
  • Fiona Oakley

      Affiliations

    • Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    • ,
  • Nian–Ling Zhu

      Affiliations

    • Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA
    • Greater Los Angeles Healthcare System, Los Angeles, CA
    • ,
  • Hidekazu Tsukamoto

      Affiliations

    • Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA
    • Greater Los Angeles Healthcare System, Los Angeles, CA
    • ,
  • Derek A. Mann

      Affiliations

    • Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom

Received 16 June 2009 ,Accepted 7 October 2009.

References 

  1. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210
  2. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007;117:539–548
  3. Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 2005;13:7–12
  4. Mann J, Oakley F, Akiboye F, et al. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ. 2007;14:275–285
  5. Hazra S, Xiong S, Wang J, et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem. 2004;279:11392–11401
  6. Miyahara T, Schrum L, Rippe R, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000;275:35715–35722
  7. Milam JE, Keshamouni VG, Phan SH, et al. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;294:L891–L901
  8. Saika S, Yamanaka O, Okada Y, et al. Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice. Am J Physiol Cell Physiol. 2007;293:C75–C86
  9. Aiello A, Pandini G, Frasca F, et al. Peroxisomal proliferator-activated receptor-gamma agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells. Endocrinology. 2006;147:4463–4475
  10. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–638
  11. Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004;14:155–164
  12. Hite KC, Adams VH, Hansen JC. Recent advances in MeCP2 structure and function. Biochem Cell Biol. 2009;87:219–227
  13. Wright MC, Issa R, Smart DE, et al. Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology. 2001;121:685–698
  14. Oakley F, Mann J, Nailard S, et al. Nuclear factor-kappaB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. Am J Pathol. 2005;166:695–708
  15. O'Neill LP, Turner BM. Immunoprecipitation of native chromatin: NChIP. Methods. 2003;31:76–82
  16. Chadwick LH, Wade PA. MeCP2 in Rett syndrome: transcriptional repressor or chromatin architectural protein?. Curr Opin Genet Dev. 2007;17:121–125
  17. Yang L, Chan CC, Kwon OS, et al. Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2006;291:G902–G911
  18. Klein ME, Lioy DT, Ma L, et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci. 2007;10:1513–1514
  19. Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005;6:838–849
  20. Fuks F, Hurd PJ, Deplus R, et al. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003;31:2305–2312
  21. Cheutin T, McNairn AJ, Jenuwein T, Gilbert DM, Singh PB, Misteli T. Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science. 2003;299:721–725
  22. Kirmizis A, Bartley SM, Kuzmichev A, et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004;18:1592–1605
  23. Chahrour M, Jung SY, Shaw C, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320:1224–1229
  24. Tan J, Yang X, Zhuang L, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–1063
  25. Douglass A, Wallace K, Parr R, et al. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J Hepatol. 2008;49:88–98
  26. Gieling RG, Burt AD, Mann DA. Fibrosis and cirrhosis reversibility - molecular mechanisms. Clin Liver Dis. 2008;12:915–937xi
  27. Ebrahimkhani MR, Elsharkawy AM, Mann DA. Wound healing and local neuroendocrine regulation in the injured liver. Expert Rev Mol Med. 2008;10:e11
  28. Houglum K, Lee KS, Chojkier M. Proliferation of hepatic stellate cells is inhibited by phosphorylation of CREB on serine 133. J Clin Invest. 1997;99:1322–1328
  29. Schwartz YB, Pirrotta V. Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet. 2007;8:9–22
  30. Weber S, Gressner OA, Hall R, et al. Genetic determinants in hepatic fibrosis: from experimental models to fibrogenic gene signatures in humans. Clin Liver Dis. 2008;12:747–757vii
  31. Rassoulzadegan M, Grandjean V, Gounon P, et al. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature. 2006;441:469–474

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism (grants R21AA016682, R24AA012885, and P50AA11999 to H.T. and D.A.M.); the Medical Research Service of Veterans Affairs; grants from the Medical Research Council, Wellcome Trust, and British Liver Trust (to D.A.M. and J.M.); and the Newcastle Health Care Charity and Newcastle upon Tyne Hospitals NHS Charity (to J.M.).

PII: S0016-5085(09)01774-0

doi: 10.1053/j.gastro.2009.10.002

Gastroenterology
Volume 138, Issue 2 , Pages 705-714.e4 , February 2010

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