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Cancer Cell. 2003 Jan;3(1):89-95.

Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene.

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The Howard Hughes Medical Institute, The Sidney Kimmel Comprehensive Cancer Center, and Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.


We attempted to answer two central questions about epigenetic silencing of the tumor suppressor gene p16(INK4a) in this study: (1) whether the maintenance of associated histone modifications is dependent on DNA methylation and (2) whether such histone modifications can occur prior to DNA methylation. By coupling chromatin immunoprecipitation with gene targeting and the analysis of specific alleles, we found that elimination of DNA methylation from a p16(INK4a) allele resulted in profound changes in surrounding histones. After continued passage of such cells, methylation of histone H3 lysine-9 occurred in conjunction with re-silencing in the absence of DNA methylation. These results have important implications for understanding the biochemical events underlying the silencing of tumor suppressor genes and the resultant growth suppression.

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