Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements.

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TítuloLoss of epigenetic silencing in tumors preferentially affects primate-specific retroelements.
Publication TypeJournal Article
Year of Publication2009
AutoresSzpakowski, S, Sun, X, Lage, JM, Dyer, A, Rubinstein, J, Kowalski, D, Sasaki, C, Costa, J, Lizardi, PM
JournalGene
Volume448
Issue2
Pagination151-67
Date Published2009 Dec 15
ISSN1879-0038
Abstract

Close to 50% of the human genome harbors repetitive sequences originally derived from mobile DNA elements, and in normal cells, this sequence compartment is tightly regulated by epigenetic silencing mechanisms involving chromatin-mediated repression. In cancer cells, repetitive DNA elements suffer abnormal demethylation, with potential loss of silencing. We used a genome-wide microarray approach to measure DNA methylation changes in cancers of the head and neck and to compare these changes to alterations found in adjacent non-tumor tissues. We observed specific alterations at thousands of small clusters of CpG dinucleotides associated with DNA repeats. Among the 257,599 repetitive elements probed, 5% to 8% showed disease-related DNA methylation alterations. In dysplasia, a large number of local events of loss of methylation appear in apparently stochastic fashion. Loss of DNA methylation is most pronounced for certain members of the SVA, HERV, LINE-1P, AluY, and MaLR families. The methylation levels of retrotransposons are discretely stratified, with younger elements being highly methylated in healthy tissues, while in tumors, these young elements suffer the most dramatic loss of methylation. Wilcoxon test statistics reveals that a subset of primate LINE-1 elements is demethylated preferentially in tumors, as compared to non-tumoral adjacent tissue. Sequence analysis of these strongly demethylated elements reveals genomic loci harboring full length, as opposed to truncated elements, while possible enrichment for functional LINE-1 ORFs is weaker. Our analysis suggests that, in non-tumor adjacent tissues, there is generalized and highly variable disruption of epigenetic control across the repetitive DNA compartment, while in tumor cells, a specific subset of LINE-1 retrotransposons that arose during primate evolution suffers the most dramatic DNA methylation alterations.

DOI10.1016/j.gene.2009.08.006
Alternate JournalGene
PubMed ID19699787
PubMed Central IDPMC2783545
Grant ListR21 CA116079-01 / CA / NCI NIH HHS / United States
R21 CA116079-01 / CA / NCI NIH HHS / United States
T15 LM07056 / LM / NLM NIH HHS / United States