Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter.
DNA methylation patterns change with age in a complex fashion, typically with an overall decrease in genomic deoxymethylcytosine (d(m)C) content, but with local increases in some promoters that contain GC-rich sequences known as CpG islands. While the consequences of age-dependent CpG island methylation have recently been studied in organs such as the colon, less is known about the functional significance of the progressive hypomethylation of promoters lacking CpG islands, and the significance of age-dependent changes in T cell DNA methylation is completely unexplored. We asked if age-dependent DNA hypomethylation might contribute to overexpression of the T cell ITGAL gene, which encodes CD11a, a subunit of LFA-1. CD11a mRNA increased with age as well as with experimentally induced DNA hypomethylation. This increase correlated with hypomethylation of sequences flanking the ITGAL promoter in vitro and in aging. 'Patch' methylation of the region suppressed promoter function. DNA methyltransferases 1 and 3a also decreased with aging. These results indicate that hypomethylation of regions flanking the ITGAL promoter may increase CD11a expression, and suggest that age-dependent hypomethylation of promoters lacking CpG islands, perhaps due to decreased DNA methyltransferase expression, may be one mechanism contributing to increased T cell gene expression with aging.
Zhang
Zhiyong
Z
Department of Medicine, Veterans Affairs Hospital, 5310 Cancer Center and Geriatrics Center Building, University of Michigan, Ann Arbor, MI 48109-0940, USA.
Deng
Chun
C
Lu
Qianjin
Q
Richardson
Bruce
B
D000328:Adult; D000368:Aged; D000375:Aging; D001426:Bacterial Proteins; D004247:DNA / Q000097:blood; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
D001426:Bacterial Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D012333:RNA, Messenger; D004247:DNA; D015254:DNA Modification Methylases; C066171:endodeoxyribonuclease AciI; C024404:BglII endonuclease; D015252:Deoxyribonucleases, Type II Site-Specific