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Cited by 127Epigenetics and DNA MethylationChromosomal and Genetic VariationsGenetic Syndromes and Imprinting

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

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Szpakowski, Sebastian, Sun, Xueguang, Lage, José M., Dyer, Andrew, Rubinstein, Jill, Kowalski, Diane, Sasaki, Clarence, Costa, Jose +1 more·2009·Gene
DOI 10.1016/j.gene.2009.08.006PMC PMC2783545
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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.

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  • Studies of methylation status in human cancers supported a model of widespread loss of epigenetic silencing also of REs, and in particular of more recently acquired groups.

    “Studies of methylation status in human cancers supported a model of widespread loss of epigenetic silencing also of REs, and in particular of more recently acquired groups 15.”

    From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [15]

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Authors
Szpakowski, S., Sun, X., Lage, J. M., Dyer, A., Rubinstein, J., Kowalski, D., Sasaki, C., Costa, J., & Lizardi, P. M.
Affiliations
Yale University (US)
Corresponding author
Lizardi, Paul M.
ORCID
Venue
Gene
Publisher
Elsevier BV
Published
2009-12
Volume
448
Issue
2
Pages
151-167
ISSN
0378-1119 (ISSN-L)
DOI
10.1016/j.gene.2009.08.006
PMC
PMC2783545
OpenAlex
W2045302592
Cited by
127
References
66
Citations by year
2026: 5 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 13 · 2016: 8 · 2015: 6 · 2014: 8 · 2013: 12 · 2012: 11
FWCI
4.16
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Yale Cancer Center
  • Swebilius Foundation
  • National Institutes of Health
  • National Cancer Institute (R21CA116079)
  • U.S. National Library of Medicine (T-15-LM07056, T15LM007056)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
DNA methylation, epigenetic silencing, LINE-1 retrotransposons, head and neck cancer, dysplasia, repetitive DNA, SVA elements
MeSH terms
Animals, Carcinoma, Squamous Cell, Head and Neck Neoplasms, Humans, Models, Biological, Neoplasms, Primates, Species Specificity, Tumor Cells, Cultured, Retroelements, CpG Islands, DNA Methylation, Endogenous Retroviruses, Long Interspersed Nucleotide Elements, Alu Elements, Oligonucleotide Array Sequence Analysis, Gene Silencing, Epigenesis, Genetic

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