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J. Biol. Chem., Vol. 276, Issue 1, 320-328, January 5, 2001
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From the The strong correlation between promoter
hypermethylation and gene silencing suggests that promoter methylation
represses transcription. To identify methylation sites that may be
critical for maintaining repression of the human HPRT gene,
we treated human/hamster hybrid cells containing an inactive human X
chromosome with the DNA demethylating agent 5-azadeoxycytidine (5aCdr),
and we then examined the high resolution methylation pattern of the
HPRT promoter in single cell-derived lines. Reactivation of
HPRT correlated with complete promoter demethylation. In
contrast, the 61 5aCdr-treated clones that failed to reactivate
HPRT exhibited sporadic promoter demethylation. However,
three specific CpG sites remained methylated in all unreactivated clones, suggesting these sites may be critical for maintaining transcriptional silencing of the HPRT gene. Re-treatment of
partially demethylated (and unreactivated) clones with a second round
of 5aCdr did not increase the frequency of HPRT
reactivation. This is consistent with mechanisms of
methylation-mediated repression requiring methylation at specific
critical sites and argues against models invoking overall levels or a
threshold of promoter methylation. Treatment of cells with the histone
deacetylase inhibitor, trichostatin A, failed to reactivate
HPRT on the inactive X chromosome, even when the promoter
was partially demethylated by 5aCdr treatment, suggesting that
transcriptional repression by DNA methylation is unlikely to depend
upon a trichostatin A-sensitive histone deacetylase.
Evidence That Silencing of the HPRT Promoter by DNA
Methylation Is Mediated by Critical CpG Sites*
§,§
**
Department of Biochemistry and Molecular
Biology, § Center for Mammalian Genetics,
Division of Pediatric Genetics, and the ¶ Department of
Statistics, University of Florida, Gainesville, Florida 32610
*
This work was supported by National Institutes of Health
Grant RO1 GM44286 (to T. P. Y.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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