Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inducing T cell LFA-1 overexpression by transfection, or by treatment with DNA methylation inhibitors including 5-azacytidine, procainamide and hydralazine, causes MHC-specific T cell autoreactivity in vitro and autoimmunity in vivo. How DNA methylation inhibitors increase LFA-1 expression is unknown. In this report we identify a mechanism by which DNA methylation affects LFA-1 expression. Nuclear run-on assays demonstrated that inhibiting DNA methylation increased transcription of CD11a but not CD18 or beta-actin mRNA. CD11a mRNA stability was not affected. Transfection of hypomethylated cells with reporter constructs containing the CD11a promoter showed no role for overexpression of transcription factors. However, the CD11a promoter demethylated following treatment with DNA methyltransferase inhibitors, and in vitro methylation of the construct suppressed its expression. Together, these results indicate that DNA methylation inhibitors can cause LFA-1 overexpression directly by demethylating the CD11a promoter. This mechanism could contribute to T cell autoreactivity, and potentially to autoimmunity.
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PMID:DNA methylation in the regulation of T cell LFA-1 expression. 1113 Jul 83

DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of autoimmunity, aging and cancer. Evidence for a role in autoimmunity comes from studies demonstrating that inhibiting T lymphocyte DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo. The autoimmunity is due in part to the heterodimeric beta(2) integrin lymphocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) overexpression, and T lymphocytes from lupus patients hypomethylate the same CD11a promoter sequences, overexpress LFA-1 and demonstrate the same autoreactivity. Procainamide and hydralazine, two drugs that cause a lupus-like disease, also inhibit T cell DNA methylation, increase LFA-1 expression and induce autoreactivity in vitro and autoimmunity in vivo, supporting the association of DNA hypomethylation and autoimmunity. Methylation patterns also change with age in T lymphocytes as well as other tissues, typically with an overall decrease in methylcytosine content, but with increases in some cytosine guanine dinucleotide (CpG) islands. Age-dependent hypomethylation contributes to LFA-1 overexpression with aging, which may play a role in the development of autoimmunity in the elderly and age-dependent methylation of CpG islands in the promoters of tumor suppressor genes is an early event in the development of some cancers. DNA hypomethylation also may contribute to carcinogenesis by promoting overexpression of proto-oncogenes, chromosomal translocations and loss of imprinting. The mechanisms causing altered DNA methylation in autoimmunity, aging and carcinogenesis are incompletely characterized but include exposure to environmental agents and drugs, diet, altered signaling in pathways regulating DNA methyltransferase expression and changes in endogenous regulatory mechanisms. Other mechanisms are likely to be identified as well.
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PMID:Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer. 1216