title: Epigenetic regulation of inflammatory gene expression in macrophages by selenium.
abstract: Acetylation of histone and non-histone proteins by histone acetyltransferases plays a pivotal role in the expression of proinflammatory genes. Given the importance of dietary selenium in mitigating inflammation, we hypothesized that selenium supplementation may regulate inflammatory gene expression at the epigenetic level. The effect of selenium towards histone acetylation was examined in both in vitro and in vivo models of inflammation by chromatin immunoprecipitation assays and immunoblotting. Our results indicated that selenium supplementation, as selenite, decreased acetylation of histone H4 at K12 and K16 in COX-2 and TNFα promoters, and of the p65 subunit of the redox sensitive transcription factor NFκB in primary and immortalized macrophages. On the other hand, selenomethionine had a much weaker effect. Selenite treatment of HIV-1-infected human monocytes also significantly decreased the acetylation of H4 at K12 and K16 on the HIV-1 promoter, supporting the down-regulation of proviral expression by selenium. A similar decrease in histone acetylation was also seen in the colonic extracts of mice treated with dextran sodium sulfate that correlated well with the levels of selenium in the diet. Bone-marrow-derived macrophages from Trsp(fl/fl)Cre(LysM) mice that lack expression of selenoproteins in macrophages confirmed the important role of selenoproteins in the inhibition of histone H4 acetylation. Our studies suggest that the ability of selenoproteins to skew the metabolism of arachidonic acid contributes, in part, to their ability to inhibit histone acetylation. In summary, our studies suggest a new role for selenoproteins in the epigenetic modulation of proinflammatory genes.
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Vivek
authors.initials: V
authors.lastname: Narayan
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Kodihalli C
authors.initials: KC
authors.lastname: Ravindra
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Chang
authors.initials: C
authors.lastname: Liao
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kaushal
authors.affiliation: Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802. Electronic address: ksprabhu@psu.edu.
authors.forename: K Sandeep
authors.initials: KS
authors.lastname: Prabhu
mesh_terms: D000107:Acetylation; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012643:Selenium / Q000172:deficiency / Q000378:metabolism* / Q000627:therapeutic use; D012645:Selenomethionine / Q000008:administration & dosage; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism*; D018038:Sodium Selenite / Q000008:administration & dosage; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C498144:Rela protein, mouse; D051140:Selenoproteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D012645:Selenomethionine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D012643:Selenium; D018038:Sodium Selenite
keywords: Cyclopentenone prostaglandins; Epigenetic regulation; Inflammatory gene expression; Selenium; Selenoproteins; p300