Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus-prone mice.
We have determined that abnormal DNA methylation in T cells coincides with the development of autoimmunity, using a mouse model that exhibits an age-dependent lupus-like disease (MRL/lpr mice). Splenic CD4(+) T cells were isolated from these mice at 5 and 16 wk of age (before and after autoimmunity is established) and the expression of DNA methyltransferase 1 (Dnmt1) and the methylation-sensitive gene Tnfsf7 (CD70) was measured. Bisulfite DNA sequencing was used to monitor the methylation status of the Tnfsf7 gene. We found that Dnmt1 steady-state mRNA levels were significantly lower in 16-wk-old MRL/lpr mice, which had established autoimmunity, compared to the 5-wk-old MRL/lpr mice. Furthermore, the expression of CD70 was higher in MRL/lpr mice at 16 wk. CD70 was overexpressed in MRL/lpr mice compared to age- and sex-matched MRL(+/+) controls. Bisulfite DNA sequencing of the Tnfsf7 gene in MRL/lpr mice revealed that at 16 wk, CG pairs were hypomethylated compared to 5-wk-old mice, and that Tnfsf7 from MRL/lpr mice was hypomethylated at 16 wk relative to age-matched MRL(+/+) controls. Our data indicate that decreased expression of Dnmt1 and the corresponding T cell DNA hypomethylation correlate with the development of age-dependent autoimmunity in MRL/lpr mice.
Sawalha
Amr H
AH
US Department of Veterans Affairs Medical Center, Oklahoma City, USA. amr-sawalha@omrf.ouhsc.edu
Jeffries
Matlock
M
D000818:Animals; D001483:Base Sequence; D053282:CD27 Ligand / Q000235:genetics* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053282:CD27 Ligand; D015254:DNA Modification Methylases