Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- T cells through epigenetic mechanisms.
An inflammatory and cytotoxic CD4+CD28- T cell subset infiltrates atherosclerotic plaques and is implicated in plaque rupture and myocardial infarctions. This pathologic subset develops with replicative stress and is found in patients with chronic inflammatory diseases such as RA as well as with aging. CD4+CD28- cells overexpress genes normally suppressed by DNA methylation in CD4+CD28+ T cells, such as KIR, perforin, and CD70. How this subset over expresses methylation-sensitive genes is unknown. DNA methylation patterns are maintained in proliferating cells by Dnmts, which are up-regulated during mitosis by the ERK and JNK signaling pathways. We hypothesized that defects in these signaling pathways contribute to altered gene expression in human CD4+CD28- cells through effects on DNA methylation. We report that signaling through the ERK and JNK pathways is decreased in CD4+CD28- relative to CD4+CD28+ cells from the same individuals and that ERK and JNK pathway inhibition decreases Dnmt1 and -3a levels, which in turn, causes demethylation and overexpression of the TNFSF7 (CD70) gene. We also report that CD4+CD28- T cells overexpress PP5, a stress-induced inhibitor of the ERK and JNK signaling pathways that may contribute to the signaling defects. We conclude that decreased ERK and JNK signaling in the CD4+CD28- subset, arising with replicative stress, can lead to the overexpression of normally suppressed genes through effects on Dnmts and consequently, chromatin structure.
Department of Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.
Yingxuan
Y
Chen
Gabriela J
GJ
Gorelik
Faith M
FM
Strickland
Bruce C
BC
Richardson
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053282:CD27 Ligand / Q000096:biosynthesis / Q000235:genetics; D018106:CD28 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000378:metabolism*
D053282:CD27 Ligand; D018106:CD28 Antigens; C505771:CD70 protein, human; D034741:RNA, Small Interfering; D004248:DNA (Cytosine-5-)-Methyltransferases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases