Intra-individual change over time in DNA methylation with familial clustering.

CONTEXT Changes over time in epigenetic marks, which are modifications of DNA such as by DNA methylation, may help explain the late onset of common human diseases. However, changes in methylation or other epigenetic marks over time in a given individual have not yet been investigated. OBJECTIVES To determine whether there are longitudinal changes in global DNA methylation in individuals and to evaluate whether methylation maintenance demonstrates familial clustering. DESIGN, SETTING, AND PARTICIPANTS We measured global DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA sampled at 2 visits on average 11 years apart in 111 individuals from an Icelandic cohort (1991 and 2002-2005) and on average 16 years apart in 126 individuals from a Utah sample (1982-1985 and 1997-2005). MAIN OUTCOME MEASURE Global methylation changes over time. RESULTS Twenty-nine percent of Icelandic individuals showed greater than 10% methylation change over time (P < .001). The family-based Utah sample also showed intra-individual changes over time, and further demonstrated familial clustering of methylation change (P = .003). The family showing the greatest global methylation loss also demonstrated the greatest loss of gene-specific methylation by a separate methylation assay. CONCLUSION These data indicate that methylation changes over time and suggest that methylation maintenance may be under genetic control.

[1]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[2]  A. Feinberg.  Epigenetics at the epicenter of modern medicine. , 2008, JAMA.

[3]  R. Jirtle,et al.  Environmental epigenomics in human health and disease , 2008, Environmental and molecular mutagenesis.

[4]  Jonathan Pevsner,et al.  DNA methylation signatures within the human brain. , 2007, American journal of human genetics.

[5]  W. Reik.  Stability and flexibility of epigenetic gene regulation in mammalian development , 2007, Nature.

[6]  A. Feinberg.  Phenotypic plasticity and the epigenetics of human disease , 2007, Nature.

[7]  V. Gudnason,et al.  Age, Gene/Environment Susceptibility-Reykjavik Study: multidisciplinary applied phenomics. , 2007, American journal of epidemiology.

[8]  T. Ekström,et al.  Impact of inflammation on epigenetic DNA methylation – a novel risk factor for cardiovascular disease? , 2007, Journal of internal medicine.

[9]  J. Mill,et al.  Molecular studies of major depressive disorder: the epigenetic perspective , 2007, Molecular Psychiatry.

[10]  J. Rogers,et al.  DNA methylation profiling of human chromosomes 6, 20 and 22 , 2006, Nature Genetics.

[11]  A. Fraser,et al.  Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways , 2006, Nature Genetics.

[12]  Frank Lyko,et al.  LUMA (LUminometric Methylation Assay)--a high throughput method to the analysis of genomic DNA methylation. , 2006, Experimental cell research.

[13]  Wei Jiang,et al.  High-throughput DNA methylation profiling using universal bead arrays. , 2006, Genome research.

[14]  R. Waterland,et al.  Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. , 2006, Human molecular genetics.

[15]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Giovannucci.  Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. , 2004, The Journal of nutrition.

[17]  Jan Bressler,et al.  Epigenetics and human disease. , 2004, Annual review of genomics and human genetics.

[18]  Andrew P Feinberg,et al.  An integrated epigenetic and genetic approach to common human disease. , 2004, Trends in genetics : TIG.

[19]  M. Leppert,et al.  Erratum: Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions (Human Molecular Genetics (2003) vol. 12 (1569-1578)) , 2004 .

[20]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[21]  B. Richardson.  DNA methylation and autoimmune disease. , 2003, Clinical immunology.

[22]  M. Leppert,et al.  Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. , 2003, Human molecular genetics.

[23]  R. Jaenisch,et al.  Induction of Tumors in Mice by Genomic Hypomethylation , 2003, Science.

[24]  A. Feinberg,et al.  Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk , 2003, Science.

[25]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[26]  Andrew P Feinberg,et al.  Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. , 2003, American journal of human genetics.

[27]  Xiangyi Lu,et al.  Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution , 2003, Nature Genetics.

[28]  A. Feinberg,et al.  Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. , 2001, Cancer research.

[29]  A. Petronis,et al.  Human morbid genetics revisited: relevance of epigenetics. , 2001, Trends in genetics : TIG.

[30]  A. Steinberg,et al.  Low expression of human histocompatibility leukocyte antigen-DR is associated with hypermethylation of human histocompatibility leukocyte antigen-DR alpha gene regions in B cells from patients with systemic lupus erythematosus. , 1985, The Journal of clinical investigation.