Transcriptional regulation of 15-lipoxygenase expression by promoter methylation.
15-Lipoxygenase type 1 (15-LO), a lipid-peroxidating enzyme implicated in physiological membrane remodeling and the pathogenesis of atherosclerosis, inflammation, and carcinogenesis, is highly regulated and expressed in a tissue- and cell-type-specific fashion. It is known that interleukins (IL) 4 and 13 play important roles in transactivating the 15-LO gene. However, the fact that they only exert such effects on a few types of cells suggests additional mechanism(s) for the profile control of 15-LO expression. In the present study, we demonstrate that hyper- and hypomethylation of CpG islands in the 15-LO promoter region is intimately associated with the transcriptional repression and activation of the 15-LO gene, respectively. The 15-LO promoter was exclusively methylated in all examined cells incapable of expressing 15-LO (certain solid tumor and human lymphoma cell lines and human T lymphocytes) while unmethylated in 15-LO-competent cells (the human airway epithelial cell line A549 and human monocytes) where 15-LO expression is IL4-inducible. Inhibition of DNA methylation in L428 lymphoma cells restores IL4 inducibility to 15-LO expression. Consistent with this, the unmethylated 15-LO promoter reporter construct exhibited threefold higher activity in A549 cells compared to its methylated counterpart. Taken together, demethylation of the 15-LO promoter is a prerequisite for the gene transactivation, which contributes to tissue- and cell-type-specific regulation of 15-LO expression.
Liu
Cheng
C
Division of Hematology, Department of Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden.
Xu
Dawei
D
Sjöberg
Jan
J
Forsell
Pontus
P
Björkholm
Magnus
M
Claesson
Hans-Erik
HE
D000107:Acetylation / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007425:Intracellular Membranes / Q000201:enzymology; D009000:Monocytes / Q000201:enzymology; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology; D015533:Transcriptional Activation / Q000235:genetics
D004791:Enzyme Inhibitors; D006657:Histones; D012333:RNA, Messenger; D012097:Repressor Proteins; D015847:Interleukin-4; D001093:Arachidonate 15-Lipoxygenase