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Enzymatic methylation of DNA in cultured human cells studied by stable isotope incorporation and mass spectrometry.

Abstract：

:Enzymatic methylation of cytosine residues in DNA, in conjunction with covalent histone modifications, establishes an epigenetic code essential for the proper control of gene expression in higher organisms. Once established during cellular differentiation, the epigenetic code must be faithfully transmitted to progeny cells. However, epigenetic perturbations can be found in most if not all cancer cells, and the mechanisms leading to these changes are not well understood. In this paper, we describe a series of experiments aimed at understanding the dynamic process of DNA methylation that follows DNA replication. Cells in culture can be propagated in the presence of (15)N-enriched uridine, which labels the pyrimidine precursor pool as well as newly replicated DNA. Simultaneous culture in the presence of (2)H-enriched methionine results in labeling of newly methylated cytosine residues. An ensemble of 5-methylcytosine residues differing in the degree of isotopic enrichment is generated, which can be examined by mass spectrometry. Using this method, we demonstrate that the kinetics of both DNA replication and methylation of newly replicated DNA are indistinguishable. The majority of methylation following DNA replication is shown to occur on the newly synthesized DNA. The method reported here does, however, suggest an unexpected methylation of parental DNA during DNA replication, which might indicate a previously undescribed chromatin remodeling process. The method presented here will be useful in monitoring the dynamic process of DNA methylation and will allow a more detailed understanding of the mechanisms of clinically used methylation inhibitors and environmental toxicants.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Herring JL,Rogstad DK,Sowers LC

doi

10.1021/tx900027w

subject

Has Abstract

pub_date

2009-06-01 00:00:00

pages

1060-8

issue

6

eissn

0893-228X

issn

1520-5010

journal_volume

22

pub_type

杂志文章

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