title: An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging.
abstract: Recent studies have demonstrated that the DNA methylome changes with age. This epigenetic drift may have deep implications for cellular differentiation and disease development. However, it remains unclear how much of this drift is functional or caused by underlying changes in cell subtype composition. Moreover, no study has yet comprehensively explored epigenetic drift at different genomic length scales and in relation to regulatory elements. Here we conduct an in-depth analysis of epigenetic drift in blood tissue. We demonstrate that most of the age-associated drift is independent of the increase in the granulocyte to lymphocyte ratio that accompanies aging and that enrichment of age-hypermethylated CpG islands increases upon adjustment for cellular composition. We further find that drift has only a minimal impact on in-cis gene expression, acting primarily to stabilize pre-existing baseline expression levels. By studying epigenetic drift at different genomic length scales, we demonstrate the existence of mega-base scale age-associated hypomethylated blocks, covering approximately 14% of the human genome, and which exhibit preferential hypomethylation in age-matched cancer tissue. Importantly, we demonstrate the feasibility of integrating Illumina 450k DNA methylation with ENCODE data to identify transcription factors with key roles in cellular development and aging. Specifically, we identify REST and regulatory factors of the histone methyltransferase MLL complex, whose function may be disrupted in aging. In summary, most of the epigenetic drift seen in blood is independent of changes in blood cell type composition, and exhibits patterns at different genomic length scales reminiscent of those seen in cancer. Integration of Illumina 450k with appropriate ENCODE data may represent a fruitful approach to identify transcription factors with key roles in aging and disease.
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China.
authors.forename: Yinming
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Center for Neurobehavioral Genetics, Los Angeles, California, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: de Jong
authors.affiliation: Center for Neurobehavioral Genetics, Los Angeles, California, USA.
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.affiliation: Medical Genomics Group, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China; Statistical Genomics Group, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D001773:Blood Cells; D001798:Blood Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D001798:Blood Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors