Effect of mitogenic stimulation and DNA methylation on human T cell DNA methyltransferase expression and activity.
DNA methylation, a mechanism modifying gene expression, is mediated in part by the enzyme DNA methyltransferase. Reduced levels of T cell DNA methyltransferase have been observed in lupus-like diseases, and increased levels have been reported in malignancies. Little is known concerning the regulation of human DNA methyltransferase. In this report we demonstrate that mitogenic T cell stimulation causes an increase in DNA methyltransferase mRNA and enzyme activity. We also show that pharmacologic inhibition of T cell DNA methylation causes an increase in the rate of DNA methyltransferase mRNA transcription and a corresponding increase in mRNA levels and enzyme activity. This suggests that DNA methyltransferase is itself regulated in part by DNA methylation status, possibly representing a feedback mechanism. DNA methylation inhibition also resulted in an increase in Ha-ras and c-jun mRNA levels, overexpression of which increases DNA methyltransferase in murine systems. These results thus identify two mechanisms regulating levels of human T cell DNA methyltransferase and raise the possibility that abnormalities in either could contribute to disorders associated with altered DNA methylation.
Yang
J
J
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
Deng
C
C
Hemati
N
N
Hanash
S M
SM
Richardson
B C
BC
D000328:Adult; D001374:Azacitidine / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D010835:Phytohemagglutinins / Q000494:pharmacology*; D011342:Procainamide / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects
D010835:Phytohemagglutinins; D012333:RNA, Messenger; D015257:DNA-Cytosine Methylases; D011342:Procainamide; D001374:Azacitidine