title: The involvement of DNA and histone methylation in the repression of IL-1β-induced MCP-1 production by hypoxia.
abstract: Hypoxia is a microenvironmental pathophysiologic factor commonly associated with tumors and tissue inflammation. We previously reported that hypoxia repressed IL-1β-induced monocyte chemoattractant protein-1 (MCP-1) expression. The purpose of this study was to investigate the mechanisms involved in the repression of MCP-1 expression under hypoxia. Treatment of HeLa cells with 5-aza-dC, an inhibitor of DNA methylation, abolished the repression of IL-1β-induced MCP-1 expression by hypoxia. A detailed study of the methylation of CpGs sites using bisulfite-sequencing PCR and 5-methylcytosine immunoprecipitation showed that hypoxia induced DNA methylation in both the enhancer and promoter regions of MCP-1in IL-1β-treated cells. Next, we analyzed histone methylation within the MCP-1 promoter and enhancer regions. The level of H3K9 di-methylation, a mark of gene repression, in both promoter and enhancer regions was increased by hypoxia in IL-1β-treated cells. Our findings suggest that changes in the methylation status of CpGs, as well as histone 3 methylation, may represent a critical event in transcriptional repression of IL-1β-induced MCP-1 expression by hypoxia. Therefore, DNA methylation is associated with not only epigenetic gene silencing, but also with transient transcriptional repression.
authors.affiliation: Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nakahama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Morita
authors.forename: Olga
authors.initials: O
authors.lastname: Safronova
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008745:Methylation; D014158:Transcription, Genetic; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D006657:Histones; D053583:Interleukin-1beta