title: H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells.
abstract: In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Bayón
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Rocío G
authors.initials: RG
authors.lastname: Urdinguio
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Estela G
authors.initials: EG
authors.lastname: Toraño
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: María G
authors.initials: MG
authors.lastname: García
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Antonella
authors.initials: A
authors.lastname: Carella
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Sandra
authors.initials: S
authors.lastname: Petrus-Reurer
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrero
authors.affiliation: Oficina de Investigación Biosanitaria (OIB-FICYT) de Asturias, 33005 Oviedo, Spain and Universidad Autónoma de Chile, Chile;
authors.forename: Pablo
authors.initials: P
authors.lastname: Martinez-Camblor
authors.affiliation: Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, 28029 Madrid, Spain;
authors.forename: Isabel
authors.initials: I
authors.lastname: Cubillo
authors.affiliation: Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, 28029 Madrid, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: García-Castro
authors.affiliation: Department of Internal Medicine, Hospital U.M. Valdecilla, University of Cantabria, IDIVAL, 39011 Santander, Spain;
authors.forename: Jesús
authors.initials: J
authors.lastname: Delgado-Calle
authors.affiliation: Department of Internal Medicine, Hospital U.M. Valdecilla, University of Cantabria, IDIVAL, 39011 Santander, Spain;
authors.forename: Flor M
authors.initials: FM
authors.lastname: Pérez-Campo
authors.affiliation: Department of Internal Medicine, Hospital U.M. Valdecilla, University of Cantabria, IDIVAL, 39011 Santander, Spain;
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
authors.affiliation: Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, 08036 Barcelona, Spain;
authors.forename: Clara
authors.initials: C
authors.lastname: Bueno
authors.affiliation: Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, 08036 Barcelona, Spain; Institut Català de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain;
authors.forename: Pablo
authors.initials: P
authors.lastname: Menéndez
authors.affiliation: MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands;
authors.forename: Anouk
authors.initials: A
authors.lastname: Mentink
authors.affiliation: Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, City of Science and Health of Turin, Regina Margherita Children's Hospital, 10126 Turin, Italy; Department of Public Health and Pediatrics, University of Turin, 10126 Turin, Italy;
authors.forename: Katia
authors.initials: K
authors.lastname: Mareschi
authors.affiliation: Translational Centre for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany;
authors.forename: Fabian
authors.initials: F
authors.lastname: Claire
authors.affiliation: Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
authors.forename: Corrado
authors.initials: C
authors.lastname: Fagnani
authors.affiliation: Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
authors.forename: Emanuela
authors.initials: E
authors.lastname: Medda
authors.affiliation: Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
authors.forename: Virgilia
authors.initials: V
authors.lastname: Toccaceli
authors.affiliation: Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
authors.forename: Sonia
authors.initials: S
authors.lastname: Brescianini
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain;
authors.forename: Sebastián
authors.initials: S
authors.lastname: Moran
authors.affiliation: Institut Català de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Catalonia, Spain;
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Translational Centre for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany; Loughborough University, Wolfson School of Mechanical and Manufacturing Engineering, LE11 3TU Loughborough, United Kingdom;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stolzing
authors.affiliation: MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands; cBITE laboratory, Merln Institute of Technology-inspired Regenerative Medicine, Maastricht University, 6200 MD Maastricht, The Netherlands;
authors.forename: Jan
authors.initials: J
authors.lastname: de Boer
authors.affiliation: Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
authors.forename: Lorenza
authors.initials: L
authors.lastname: Nisticò
authors.affiliation: Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
authors.forename: Maria A
authors.initials: MA
authors.lastname: Stazi
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain; Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, 28049 Madrid, Spain mffraga@cnb.csic.es affernandez@hca.es.
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D017422:Sequence Analysis, DNA; D013234:Stem Cells / Q000166:cytology*; D014430:Twins, Monozygotic; D055815:Young Adult
chemical_list: D002843:Chromatin; D006657:Histones; D004247:DNA