Identification, replication and characterization of epigenetic remodelling in the aging genome: a cross population analysis

Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWER <0.05, 86% demethylated with increasing age. Double-replication resulted in 5,168 CpGs (39% age-methylated and 61% age-demethylated) which were characterized by high concentration of age-methylated CpGs at 1stExon and TSS200 and a dominant pattern of age-demethylated CpGs at other gene regions, and by overwhelming age-related methylation in CpG islands and demethylation at shore/shelf and open sea. The differential distribution patterns over gene regions for methylated and demethylated CpGs both relate to reduced gene activity during aging. Pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations particularly linked to functions of the extracellular matrix, all implicated in the aging process and age-related disease risk.

[1]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[2]  A. Moore,et al.  Change in Epigenome-Wide DNA Methylation Over 9 Years and Subsequent Mortality: Results From the InCHIANTI Study. , 2016, The journals of gerontology. Series A, Biological sciences and medical sciences.

[3]  S. Horvath,et al.  Aging effects on DNA methylation modules in human brain and blood tissue , 2012, Genome Biology.

[4]  S. Horvath.  DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[5]  J. Tyler,et al.  Epigenetics and aging , 2016, Science Advances.

[6]  Hermann Brenner,et al.  Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. , 2014, Human molecular genetics.

[7]  Ian J Deary,et al.  Cohort profile: the Lothian Birth Cohorts of 1921 and 1936. , 2012, International journal of epidemiology.

[8]  L. Christiansen,et al.  Differential and correlation analyses of microarray gene expression data in the CEPH Utah families. , 2008, Genomics.

[9]  Robin M. Murray,et al.  Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population , 2012, PLoS genetics.

[10]  E. Feierstein,et al.  DNA Methylation of the First Exon Is Tightly Linked to Transcriptional Silencing , 2011, PloS one.

[11]  M McGue,et al.  A Danish Population-Based Twin Study on General Health in the Elderly , 1999, Journal of aging and health.

[12]  M. Nykter,et al.  Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression , 2015, BMC Genomics.

[13]  I. Krantz,et al.  Characterization of DNA methylation and its association with other biological systems in lymphoblastoid cell lines. , 2012, Genomics.

[14]  C. Franceschi,et al.  Reconfiguration of DNA methylation in aging , 2015, Mechanisms of Ageing and Development.

[15]  Ulf Gyllensten,et al.  Continuous Aging of the Human DNA Methylome Throughout the Human Lifespan , 2013, PloS one.

[16]  L. Christiansen,et al.  Epigenetic signature of birth weight discordance in adult twins , 2014, BMC Genomics.

[17]  I. Deary,et al.  Alzheimer's Disease Genes Are Associated with Measures of Cognitive Ageing in the Lothian Birth Cohorts of 1921 and 1936 , 2011, International journal of Alzheimer's disease.

[18]  Gangning Liang,et al.  Gene body methylation can alter gene expression and is a therapeutic target in cancer. , 2014, Cancer cell.

[19]  H. Qing,et al.  G Protein-Coupled Receptors (GPCRs) in Alzheimer’s Disease: A Focus on BACE1 Related GPCRs , 2016, Front. Aging Neurosci..

[20]  J. Labat-Robert,et al.  Cell–matrix interactions in aging: role of receptors and matricryptins , 2004, Ageing Research Reviews.

[21]  L. Christiansen,et al.  Epigenetic drift in the aging genome: a ten-year follow-up in an elderly twin cohort. , 2016, International journal of epidemiology.

[22]  J. Phillip,et al.  The Mechanobiology of Aging. , 2015, Annual review of biomedical engineering.

[23]  T. Ideker,et al.  Genome-wide methylation profiles reveal quantitative views of human aging rates. , 2013, Molecular cell.

[24]  Gastone Castellani,et al.  Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes , 2011, AGE.

[25]  P. Mozetic,et al.  The role of extracellular matrix in age-related conduction disorders: a forgotten player? , 2015, Journal of geriatric cardiology : JGC.

[26]  R. Irizarry,et al.  Accounting for cellular heterogeneity is critical in epigenome-wide association studies , 2014, Genome Biology.

[27]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..