title: Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes.
abstract: BACKGROUND
  Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip.
  
  
  RESULTS
  After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within -5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm.
  
  
  CONCLUSIONS
  This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.
authors: Department of Medicine Solna, Translational Immunology Unit, Karolinska University Hospital, Stockholm, Sweden ; Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Nathalie
authors: N
authors: Acevedo
authors: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Lovisa E
authors: LE
authors: Reinius
authors: Department of Biology, Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark.
authors: Morana
authors: M
authors: Vitezic
authors: Unit of Systems Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
authors: Vittorio
authors: V
authors: Fortino
authors: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Cilla
authors: C
authors: Söderhäll
authors: Department of Virology, School of Medicine, University of Tampere, Tampere, Finland.
authors: Hanna
authors: H
authors: Honkanen
authors: Department of Pediatrics, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors: Riitta
authors: R
authors: Veijola
authors: Department of Pediatrics, Turku University Hospital, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
authors: Olli
authors: O
authors: Simell
authors: Department of Physiology and Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
authors: Jorma
authors: J
authors: Toppari
authors: Immunogenetics Laboratory, University of Turku, Finland and Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
authors: Jorma
authors: J
authors: Ilonen
authors: Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland ; Department of Paediatrics, Tampere University Hospital, Tampere, Finland ; Folkhälsan Institute of Genetics, Helsinki, and Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors: Mikael
authors: M
authors: Knip
authors: Department of Medicine Solna, Translational Immunology Unit, Karolinska University Hospital, Stockholm, Sweden.
authors: Annika
authors: A
authors: Scheynius
authors: Department of Virology, School of Medicine, University of Tampere, Tampere, Finland ; Fimlab Laboratories, Tampere, Finland.
authors: Heikki
authors: H
authors: Hyöty
authors: Unit of Systems Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
authors: Dario
authors: D
authors: Greco
authors: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden ; Folkhälsan Institute of Genetics, Helsinki, and Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors: Juha
authors: J
authors: Kere
keywords: Age-modified CpG; Childhood; DNA methylation; Genes; Leukocytes; Longitudinal