Affiliation:
1. Department of Microbiology and Immunology, Weill Cornell Medicine, 1300 York Ave, New York, NY 10065, United States
Abstract
Background:
MGMT (O6-methylguanine-DNA methyltransferase) is primarily responsible
for limiting the activity of some widely used chemotherapeutic agents, including temozolomide
(TMZ) and carmustine (BCNU). The gene encoding this protein is epigenetically regulated,
and assessment of methylation at its promoter region is used to predict glioma patients’ response to
TMZ.
Methods:
In this report, we employed a bioinformatic approach to elucidate MGMT’s epigenetic
regulation. Integrated for the analysis were genome-wide methylation and transcription datasets for
> 8,600 human tissue (representing 31 distinct cancer types) and 500 human cancer cell line samples.
Also crucial to the interpretation of results were publicly available data from the ENCODE
Project: tracks for histone modifications (via ChIP-seq) and DNase I hypersensitivity (via DNaseseq),
as well as methylation and transcription data for representative cell lines (HeLa-S3, HMEC,
K562).
Results and Discussion:
We were able to validate (perhaps more comprehensively) the contrasting
influences of CpG methylation at promoter region and at gene body on MGMT transcription.
While the MGMT promoter is populated by CpG sites whose methylation levels displayed high negative
correlation (R) with MGMT mRNA counts, the gene body harbors CpG sites exhibiting high
positive R values. The promoter CpG sites with very high negative R’s across cancer types include
cg12981137, cg12434587, and cg00618725. Among the notable gene body CpG sites (high positive
R’s across cancer types) are cg00198994 (Intron 1), cg04473030 (Intron 2), and cg07367735
(Intron 4). For certain cancer types, such as melanoma, gene body methylation appears to be a better
predictor of MGMT transcription (compared to promoter methylation). In general, the CpG
methylation v. MGMT expression R values are higher in cell lines relative to tissues. Also, these
correlations are noticeably more prominent in certain cancer types such as colorectal, adrenocortical,
esophageal, skin, and head and neck cancers, as well as glioblastoma. As expected, hypomethylation
at the promoter region is associated with more open chromatin, and enrichment of histone
marks H3K4m1, H3K4m2, H3K4m3, and H3K9ac.
Conclusion:
Overall, our analysis illustrated the contrasting influence of promoter and gene body
methylation on MGMT expression. These observations may help improve diagnostic assays for
MGMT.
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Drug Discovery,Pharmacology,Oncology
Cited by
5 articles.
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