Research Papers: Gerotarget (Focus on Aging):

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

Shu-Hui Yeh _, Cheng-Ling Liu, Ren-Chieh Chang, Chih-Chiang Wu, Chia-Hsueh Lin and Kuender D. Yang

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Oncotarget. 2017; 8:48591-48602. https://doi.org/10.18632/oncotarget.18109

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Shu-Hui Yeh1,*, Cheng-Ling Liu2,*, Ren-Chieh Chang3, Chih-Chiang Wu4, Chia-Hsueh Lin5 and Kuender D. Yang1,4,5

1 Graduate Institute of Long-Term Care, MacKay Medical College, New Taipei City, Taiwan

2 Department of Medical Research and Development, Show Chwan Memorial Hospital at Chang Bing, Changhua, Taiwan

3 Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

4 Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan

5 Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan

* Shu-Hui Yeh and Cheng-Ling Liu equally contributed to this study

Correspondence to:

Kuender D. Yang, email:

Keywords: aging, epigenetic, DNA hypermethylation, T cell differentiation, GSTM1, Gerotarget

Received: July 16, 2016 Accepted: May 10, 2017 Published: May 23, 2017


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.

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