H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells
- Agustín F Fernández1,
- Gustavo F Bayón1,
- Rocío G Urdinguio1,
- Estela G Toraño1,
- María G García1,
- Antonella Carella1,
- Sandra Petrus-Reurer1,
- Cecilia Ferrero1,
- Pablo Martinez-Camblor2,
- Isabel Cubillo3,
- Javier García-Castro3,
- Jesús Delgado-Calle4,
- Flor M Pérez-Campo4,
- José A Riancho4,
- Clara Bueno5,
- Pablo Menéndez5,
- Anouk Mentink6,
- Katia Mareschi7,
- Fabian Claire8,
- Corrado Fagnani9,
- Emanuela Medda9,
- Virgilia Toccaceli9,
- Sonia Brescianini9,
- Sebastián Moran10,
- Manel Esteller10,
- Alexandra Stolzing8,
- Jan de Boer6,
- Lorenza Nisticó9,
- Maria A Stazi9 and
- Mario F Fraga11,12
- 1 Universidad de Oviedo;
- 2 Unidad de Apoyo a la Investigación CAIBER;
- 3 Instituto de Salud Carlos III;
- 4 University of Cantabria;
- 5 University of Barcelona;
- 6 University of Twente;
- 7 University of Turin;
- 8 University Leipzig;
- 9 Istituto Superiore di Sanitá;
- 10 Bellvitge Biomedical Research Institute (IDIBELL);
- 11 National Centre of Biotechnology
- ↵* Corresponding author; email: mffraga{at}cnb.csic.es
Abstract
In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational 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 obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 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 non-genetic 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.
- Received October 31, 2013.
- Accepted September 23, 2014.
- Published by Cold Spring Harbor Laboratory Press
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