Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context.
Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island-dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations.
Christensen
Brock C
BC
Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Houseman
E Andres
EA
Marsit
Carmen J
CJ
Zheng
Shichun
S
Wrensch
Margaret R
MR
Wiemels
Joseph L
JL
Nelson
Heather H
HH
Karagas
Margaret R
MR
Padbury
James F
JF
Bueno
Raphael
R
Sugarbaker
David J
DJ
Yeh
Ru-Fang
RF
Wiencke
John K
JK
Kelsey
Karl T
KT
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity
Nat Rev Genet. 2002 Jun;3(6):415-28
12042769
Cancer Res. 2009 Jan 1;69(1):227-34
19118007
Carcinogenesis. 2009 Mar;30(3):416-22
19126652
Carcinogenesis. 2007 Aug;28(8):1745-51
17522068
Cancer Epidemiol Biomarkers Prev. 2007 Jan;16(1):108-14
17220338
Cancer Epidemiol Biomarkers Prev. 2005 Feb;14(2):476-82
15734975
Cytogenet Genome Res. 2004;105(2-4):325-34
15237220
Annu Rev Genet. 2004;38:305-45
15568979
PLoS Biol. 2008 Jan;6(1):e22
18232738
Bioinformatics. 2008 Mar 1;24(5):719-20
18024473
Environ Health Perspect. 1998 Aug;106 Suppl 4:1047-50
9703491
PLoS Biol. 2004 Dec;2(12):e405
15550986
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18654-9
18003927
Nucleic Acids Res. 2004 Feb 18;32(3):e38
14973332
Biometrics. 1986 Mar;42(1):121-30
3719049
Radiat Res. 2007 Oct;168(4):409-14
17903034
PLoS One. 2007 Sep 19;2(9):e895
17878930
Carcinogenesis. 2008 Aug;29(8):1555-9
18310086
Nat Genet. 1994 Aug;7(4):536-40
7951326
Nat Struct Mol Biol. 2009 May;16(5):564-71
19377480
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3740-5
11891299
Nat Rev Cancer. 2004 Feb;4(2):143-53
14732866
Am J Hum Genet. 2002 Mar;70(3):604-11
11813134
Biometrics. 2006 Dec;62(4):1062-70
17156280
Bioinformatics. 2004 Aug 12;20(12):1896-904
15044245
Ann N Y Acad Sci. 2007 Apr;1100:60-74
17460165
Bioinformatics. 2005 May 1;21(9):2118-22
15713737
Nature. 1999 Nov 11;402(6758):187-91
10647011
Mech Ageing Dev. 2002 Sep;123(11):1487-503
12425956
Genomics. 2007 Sep;90(3):314-23
17582736
Nat Genet. 1999 Oct;23(2):185-8
10508514
Hum Mol Genet. 2008 Oct 15;17(R2):R156-65
18852205
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9
16009939
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1172-7
17548681
Genome Res. 2006 Mar;16(3):383-93
16449502
JAMA. 2008 Jun 25;299(24):2877-83
18577732
Int J Cancer. 2003 Jan 10;103(2):153-60
12455028
Int J Cancer. 2006 Oct 15;119(8):1761-6
16708382
Int J Cancer. 2002 Apr 1;98(4):609-15
11920623
Ageing Res Rev. 2003 Jul;2(3):245-61
12726774
PLoS Genet. 2006 Mar;2(3):e26
16520826
Clin Cancer Res. 2007 Jul 1;13(13):3796-802
17606710
Cancer Res. 1995 Nov 1;55(21):4910-4
7585529
Genome Res. 2008 Sep;18(9):1518-29
18577705
Clin Immunol. 2003 Oct;109(1):103-8
14585281
Mol Cell Biol. 2009 May;29(9):2409-18
19273604
BMC Bioinformatics. 2008 Sep 09;9:365
18782434
Nat Genet. 2006 Dec;38(12):1378-85
17072317
J Natl Cancer Inst. 2005 Sep 21;97(18):1330-8
16174854