H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

  1. Mario F. Fraga1,16
  1. 1Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
  2. 2Oficina de Investigación Biosanitaria (OIB-FICYT) de Asturias, 33005 Oviedo, Spain and Universidad Autónoma de Chile, Chile;
  3. 3Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, 28029 Madrid, Spain;
  4. 4Department of Internal Medicine, Hospital U.M. Valdecilla, University of Cantabria, IDIVAL, 39011 Santander, Spain;
  5. 5Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, 08036 Barcelona, Spain;
  6. 6Institut Català de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain;
  7. 7MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands;
  8. 8Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, City of Science and Health of Turin, Regina Margherita Children’s Hospital, 10126 Turin, Italy;
  9. 9Department of Public Health and Pediatrics, University of Turin, 10126 Turin, Italy;
  10. 10Translational Centre for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany;
  11. 11Genetic Epidemiology Unit, National Centre of Epidemiology, Surveillance and Health Promotion; Istituto Superiore di Sanità; Viale Regina Elena 299, 00161, Rome, Italy;
  12. 12Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain;
  13. 13Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Catalonia, Spain;
  14. 14Loughborough University, Wolfson School of Mechanical and Manufacturing Engineering, LE11 3TU Loughborough, United Kingdom;
  15. 15cBITE laboratory, Merln Institute of Technology-inspired Regenerative Medicine, Maastricht University, 6200 MD Maastricht, The Netherlands;
  16. 16Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, 28049 Madrid, Spain
  1. Corresponding authors: mffraga{at}cnb.csic.es, affernandez{at}hca.es

  1. ↵17 These authors contributed equally to this work.

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.

Footnotes

  • Received October 31, 2013.
  • Accepted September 23, 2014.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

| Table of Contents

This Article

  1. Published in Advance September 30, 2014, doi: 10.1101/gr.169011.113 Genome Res. 25: 27-40 © 2015 Fernández et al.; Published by Cold Spring Harbor Laboratory Press

Article Category

Share

Preprint Server



Current Issue

  1. March 2024, 34 (3)
  1. Current Issue
  1. Alert me to new issues of Genome Research