title: Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements.
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.
authors.affiliation: Interdepartmental Program in Computational, Biology and Bioinformatics, Yale University School of Medicine, Room LH-208, 310 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Szpakowski
authors.forename: Xueguang
authors.initials: X
authors.lastname: Sun
authors.forename: José M
authors.initials: JM
authors.lastname: Lage
authors.forename: Andrew
authors.initials: A
authors.lastname: Dyer
authors.forename: Jill
authors.initials: J
authors.lastname: Rubinstein
authors.forename: Diane
authors.initials: D
authors.lastname: Kowalski
authors.forename: Clarence
authors.initials: C
authors.lastname: Sasaki
authors.forename: Jose
authors.initials: J
authors.lastname: Costa
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lizardi
mesh_terms: D020087:Alu Elements / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology; D020077:Endogenous Retroviruses / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011323:Primates / Q000235:genetics*; D018626:Retroelements / Q000235:genetics*; D013045:Species Specificity; D014407:Tumor Cells, Cultured
chemical_list: D018626:Retroelements
references.citation: Nat Genet. 2002 Jun;31(2):159-65
references.pmid: 12006980
references.citation: Genes Cells. 2007 Oct;12(10):1101-10
references.pmid: 17903170
references.citation: DNA Repair (Amst). 2007 Jul 1;6(7):923-35
references.pmid: 17363343
references.citation: Mol Cancer. 2004 Apr 26;3:12
references.pmid: 15109395
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3740-5
references.pmid: 11891299
references.citation: Gene. 2007 Apr 1;390(1-2):130-5
references.pmid: 16987613
references.citation: Nucleic Acids Res. 1999 Jan 15;27(2):573-80
references.pmid: 9862982
references.citation: Int J Cancer. 2007 Jan 1;120(1):81-90
references.pmid: 17013901
references.citation: Nat Genet. 2002 Jun;31(2):126-7
references.pmid: 12006979
references.citation: Genome Res. 2003 Feb;13(2):294-307
references.pmid: 12566408
references.citation: J Mol Biol. 2005 Dec 9;354(4):994-1007
references.pmid: 16288912
references.citation: Science. 2007 May 4;316(5825):744-7
references.pmid: 17446352
references.citation: Genes Chromosomes Cancer. 2006 Jan;45(1):1-10
references.pmid: 16175572
references.citation: Science. 2005 Oct 14;310(5746):321-4
references.pmid: 16224025
references.citation: Mol Cell. 2008 Sep 26;31(6):785-99
references.pmid: 18922463
references.citation: Methods Mol Biol. 2006;342:129-38
references.pmid: 16957372
references.citation: J Mol Evol. 2004 Nov;59(5):642-56
references.pmid: 15693620
references.citation: Methods Mol Biol. 2006;342:295-312
references.pmid: 16957384
references.citation: J Gen Virol. 1984 May;65 ( Pt 5):887-98
references.pmid: 6202829
references.citation: Hum Mutat. 2007 Jun;28(6):527-39
references.pmid: 17309057
references.citation: Nucleic Acids Res. 1993 May 11;21(9):2252
references.pmid: 8502570
references.citation: Neoplasia. 2008 Jun;10(6):521-33
references.pmid: 18516289
references.citation: Int J Cancer. 2007 Oct 15;121(8):1724-8
references.pmid: 17582607
references.citation: Nucleic Acids Res. 1993 Apr 25;21(8):1863-72
references.pmid: 8388099
references.citation: Genomics. 2009 Mar;93(3):205-12
references.pmid: 18951971
references.citation: Br J Cancer. 1999 Jul;80(9):1312-21
references.pmid: 10424731
references.citation: Arch Virol. 2006 Nov;151(11):2215-28
references.pmid: 16830071
references.citation: Cell. 2007 Mar 23;128(6):1089-103
references.pmid: 17346786
references.citation: Mutat Res. 2004 Apr 14;548(1-2):117-25
references.pmid: 15063142
references.citation: Genomics. 2002 May;79(5):628-34
references.pmid: 11991712
references.citation: Exp Cell Res. 2009 Mar 10;315(5):849-62
references.pmid: 19167380
references.citation: Genome Res. 2003 Oct;13(10):2306-15
references.pmid: 12975312
references.citation: Mol Cell Biol. 2001 Mar;21(6):1973-85
references.pmid: 11238933
references.citation: Nucleic Acids Res. 2007;35(11):3741-51
references.pmid: 17517773
references.citation: Mol Cell Biol. 2000 Jan;20(1):54-60
references.pmid: 10594008
references.citation: Oncogene. 2007 Jun 21;26(29):4226-33
references.pmid: 17237820
references.citation: Oncogene. 2005 Nov 3;24(48):7213-23
references.pmid: 16170379
references.citation: Genome Res. 2007 Apr;17(4):422-32
references.pmid: 17339369
references.citation: Clin Cancer Res. 2001 Jun;7(6):1553-60
references.pmid: 11410490
references.citation: Nat Genet. 2008 Sep;40(9):1124-9
references.pmid: 19165926
references.citation: Hum Genomics. 2004 Mar;1(3):167-78
references.pmid: 15588477
references.citation: J Mol Biol. 2004 Nov 26;344(3):675-82
references.pmid: 15533437
references.citation: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D498-500
references.pmid: 15608246
references.citation: Genome Res. 2002 Apr;12(4):656-64
references.pmid: 11932250
references.citation: Genome Res. 2006 Jan;16(1):78-87
references.pmid: 16344559
references.citation: Cell. 2008 Oct 3;135(1):192-192.e1
references.pmid: 18854165
references.citation: Virology. 2002 Nov 10;303(1):164-73
references.pmid: 12482668
references.citation: Am J Phys Anthropol. 2007;Suppl 45:2-19
references.pmid: 18046749
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5261-6
references.pmid: 11959976
references.citation: Melanoma Res. 2006 Jun;16(3):223-34
references.pmid: 16718269
references.citation: Int J Colorectal Dis. 2004 Mar;19(2):95-101
references.pmid: 14534800
references.citation: Nat Rev Genet. 2002 May;3(5):370-9
references.pmid: 11988762
references.citation: Hum Mol Genet. 2009 Apr 1;18(7):1221-8
references.pmid: 19147684
references.citation: Nature. 2009 Mar 12;458(7235):223-7
references.pmid: 19182780
references.citation: Curr Opin Struct Biol. 1998 Jun;8(3):333-7
references.pmid: 9666329
references.citation: J Mol Evol. 1996 Jan;42(1):59-65
references.pmid: 8576965
references.citation: Cancer Res. 2003 Dec 15;63(24):8735-41
references.pmid: 14695188
references.citation: Cancer Immun. 2004 Feb 11;4:2
references.pmid: 14871062
references.citation: Cancer Immun. 2008 Jun 27;8:11
references.pmid: 18581998
references.citation: APMIS. 1998 Jan;106(1):216-20
references.pmid: 9524581
references.citation: Nucleic Acids Res. 2008 Feb;36(3):770-84
references.pmid: 18084025
references.citation: Cancer. 2003 Jul 1;98(1):187-97
references.pmid: 12833471
references.citation: Genes Dev. 2008 Apr 1;22(7):908-17
references.pmid: 18381894