title: Non-linear patterns in age-related DNA methylation may reflect CD4+T cell differentiation.
abstract: DNA methylation (DNAm) is an important epigenetic process involved in the regulation of gene expression. While many studies have identified thousands of loci associated with age, few have differentiated between linear and non-linear DNAm trends with age. Non-linear trends could indicate early- or late-life gene regulatory processes. Using data from the Illumina 450K array on 336 human peripheral blood samples, we identified 21 CpG sites that associated with age (P<1.03E-7) and exhibited changing rates of DNAm change with age (P<1.94E-6). For 2 of these CpG sites (cg07955995 and cg22285878), DNAm increased with age at an increasing rate, indicating that differential DNAm was greatest among elderly individuals. We observed significant replication for both CpG sites (P<5.0E-8) in a second set of peripheral blood samples. In 8 of 9 additional data sets comprising samples of monocytes, T cell subtypes, and brain tissue, we observed a pattern directionally consistent with DNAm increasing with age at an increasing rate, which was nominally significant in the 3 largest data sets (4.3E-15<P<0.039). cg07955995 and cg22285878 reside in the promoter region of KLF14, which encodes a protein involved in immune cell differentiation via the repression of FOXP3. These findings may suggest a possible role for cg07955995 and cg22285878 in immunosenescence.
authors.affiliation: a Department of Human Genetics , Emory University , Atlanta , GA , USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Johnson
authors.affiliation: b Department of Epidemiology , University of Alabama at Birmingham , Birmingham , AL , USA.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Wiener
authors.affiliation: c Department of Gynecology and Obstetrics , Emory University , Atlanta , GA , USA.|d Department of Psychiatry and Behavioral Sciences , Emory University , Atlanta , GA , USA.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
authors.affiliation: c Department of Gynecology and Obstetrics , Emory University , Atlanta , GA , USA.|d Department of Psychiatry and Behavioral Sciences , Emory University , Atlanta , GA , USA.
authors.forename: Shota
authors.initials: S
authors.lastname: Nishitani
authors.affiliation: e HudsonAlpha Institute for Biotechnology , Huntsville , AL , USA.
authors.forename: Devin M
authors.initials: DM
authors.lastname: Absher
authors.affiliation: f College of Public Health , University of Kentucky , Lexington , KY , USA.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: b Department of Epidemiology , University of Alabama at Birmingham , Birmingham , AL , USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: a Department of Human Genetics , Emory University , Atlanta , GA , USA.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic
keywords: Aging; DNA methylation; FOXP3, immunosenescence; KLF14