Aging-dependent DNA hypermethylation and gene expression of GSTM1 involved in T cell differentiation

Abstract

This study investigated whether aging was associated with epigenetic changes of DNA hypermethylation on immune gene expression and lymphocyte differentiation. We screened CG sites of methylation in blood leukocytes from different age populations, picked up genes with age-related increase of CG methylation content more than 15%, and validated immune related genes with CG hypermethylation involved in lymphocyte differentiation in the aged population. We found that 12 genes (EXHX1、 IL-10、 TSP50、 GSTM1、SLC5A5、SPI1、F2R、LMO2、PTPN6、FGFR2、MMP9、MET) were associated with promoter or exon one DNA hypermethylation in the aged group. Two immune related genes, GSTM1 and LMO2, were chosen to validate its aging-related CG hypermethylation in different leukocytes. We are the first to validate that GSTM1_P266 and LMO2_E128 CG methylation contents in T lymphocytes but not polymorphonuclear cells (PMNs) or mononuclear cells (MNCs) were significantly increased in the aged population. The GSTM1 mRNA expression in T lymphocytes but not PMNs or MNCs was inversely associated with the GSTM1 CG hypermethylation levels in the aged population studied. Further studies showed that lower GSTM1 CG methylation content led to the higher GSTM1 mRNA expression in T cells and knockdown of GSTM1 mRNA expression decreased type 1 T helper cell (Th1) differentiation in Jurkat T cells and normal adult CD4 T cells. The GSTM1_P266 hypermethylation in the aged population associated with lower GSTM1 mRNA expression was involved in Th1 differentiation, highlighting that modulation of aging-associated GSTM1 methylation may be able to enhance T helper cell immunity in the elders.

Immune senescence, epigenetics and autoimmunity

“…While epigenetic changes in aging result in largely unpredictable changes in gene expression, some of these likely represent unidirectional adaptive changes that contribute to the basic biological underpinning of aging [83, 84]. Recent studies focusing on transcriptomic approaches have confirmed that age-associated methylation changes vary depending on the specific leukocyte populations and T cell subsets [85, 86]. Amongst the various immune cell populations, the T cell compartment may be most affected by the aging process [86, 87].…”

Determination of epigenetic age through DNA methylation of NPTX2 gene using buccal scrapes: A pilot study

“…[ 11 16 17 18 20 ] The same studies showed an increase in the percentage of methylation of this gene with age. [ 11 16 17 18 20 ] The percentage of hypermethylation was calculated manually. This was done in contrast to different studies that used software to do the same.…”

“…Among these genes, NPTX2 methylation status was shown to be linked with age in blood as well. [ 17 ]…”

Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

“…Interestingly, in patients with anaplastic astrocytoma as well as oligodendroglioma, the GSTM1-null genotype, in combination with a specific homozygous GSTM1 allelic variant, infers superior survival and increased chemotherapy-related toxicity (30). More recent studies have associated GSTM1 mRNA levels with type 1 Th cell differentiation in aging (31), suggesting that GSTM1 deficiency may effect CD4 T cell function. The exact mechanism of GSTM1 and if GSTM1 deletion is a predictor of vaccination response in children with recurrent LGG remain to be elucidated in a larger cohort.…”