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Reactivation of a silenced H19 gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation

  • Lynch, Catherine A1
  • Tycko, Benjamin2
  • Bestor, Timothy H3
  • Walsh, Colum P1
  • 1 University of Ulster, Cancer and Ageing Research Group, School of Biomedical Sciences, Coleraine, BT52 1SA, United Kingdom , Coleraine
  • 2 Russ Berie Research Pavillion, Columbia University, Institute of Cancer Genetics, 1150 St. Nicholas Avenue, New York, 10032, USA , New York
  • 3 Columbia University, Department of Genetics and Development, College of Physicians and Surgeons, New York, NY10032, USA , New York
Published Article
Molecular Cancer
Springer (Biomed Central Ltd.)
Publication Date
Jul 11, 2002
DOI: 10.1186/1476-4598-1-2
Springer Nature


BackgroundThe active copy of the imprinted gene H19 is turned off by inappropriate methylation in several pediatric tumors including Wilms' Tumour and embryonal rhabdomyosarcoma. H19 controls in cis the linked Insulin-like Growth Factor 2 (IGF2) gene, encoding an important growth factor. Recent work has suggested that methylation of a gene may lead to deacetylation of its associated histones and that silenced genes can be reactivated by increasing histone acetylation levels.ResultsTreatment of a rhabdomyosarcoma cell line which has a silent, methylated H19 gene with histone deacetylase (HDAC) inhibitors under conditions which gave maximal hyperacetylation of histone 4, both globally and at the H19 gene itself could not reactivate H19 or affect the active Insulin-like Growth Factor 2 (IGF2) gene, but caused clear up-regulation of the Tissue-type Plasminogen Activator (TPA) gene, a non-imprinted gene known to respond to changes in histone acetylation. In contrast, mild treatment of the cells with the methylation inhibitor 5-AzaC-2'-deoxycytidine (AzaC) on its own was able to reactivate H19. Combining AzaC treatment with HDAC inhibitors gave a reduced rather than enhanced reactivation. These findings were confirmed in mouse primary liver and kidney explants which maintain normal imprinting, where we also found that the silent Igf2 gene could not be reactivated by HDAC inhibitors.ConclusionThese results suggest that DNA methylation rather than histone acetylation is the primary determinant of silencing of H19 in rhabdomyosarcoma.

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