Age-associated DNA methylation changes in naive CD4+T cells suggest an evolving autoimmune epigenotype in aging T cells.
We sought to define age-associated DNA methylation changes in naive CD4+T cells.



Naive CD4+T cells were collected from 74 healthy individuals (age 19-66 years), and age-related DNA methylation changes were characterized.



We identified 11,431 age-associated CpG sites, 57% of which were hypermethylated with age. Hypermethylated sites were enriched in CpG islands and repressive transcription factor binding sites, while hypomethylated sites showed T cell specific enrichment in active enhancers marked by H3K27ac and H3K4me1. Our data emphasize cancer-related DNA methylation changes with age, and also reveal age-associated hypomethylation in immune-related pathways, such as T cell receptor signaling, FCγR-mediated phagocytosis, apoptosis and the mammalian target of rapamycin signaling pathway. The MAPK signaling pathway was hypermethylated with age, consistent with a defective MAPK signaling in aging T cells.



Age-associated DNA methylation changes may alter regulatory mechanisms and signaling pathways that predispose to autoimmunity.
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
Mikhail G
MG
Dozmorov
Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Patrick
P
Coit
Division of Rheumatology, Henry Ford Health System, Detroit, MI 48202, USA.
Kathleen
K
Maksimowicz-McKinnon
Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Center for Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Amr H
AH
Sawalha
D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D015551:Autoimmunity; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018899:CpG Islands; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D014157:Transcription Factors
CD4+ T cells; EZH2; PRC2; aging; autoimmunity; epigenetics; lupus; mTOR; methylation