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Selenium inhibits the histone acetyltransferase (HAT) activity of KAT3B in macrophages
Author(s) -
Narayan Vivek,
Kodihalli Ravindra,
Prabhu K. Sandeep
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1022.2
Subject(s) - epigenetics , acetylation , histone , histone acetyltransferase , proinflammatory cytokine , histone acetyltransferases , gene expression , biology , biochemistry , gene , microbiology and biotechnology , chemistry , inflammation , immunology
Abnormal regulation of epigenetic modifications forms the underlying basis of overexpression of inflammatory genes, and is a key component in several diseases including cancer and AIDS. The ability of nutrients to modulate epigenetic regulatory processes has offered potential explanations as to the role of diet in modifying disease risk. We have discovered a novel mechanism of epigenetic control by the micronutrient selenium (Se) in murine macrophages that could negatively impact the overexpression of proinflammatory genes. Supplementation of an endotoxins‐timulated murine macrophage cell‐line resulted in a significant decrease in the acetylation of histones and the non‐histone protein p65. Our studies demonstrate that Se inhibits the HAT activity of KAT3B (p300) via the modulation of cyclooxygenase (COX) pathway that involved Se‐dependent production of a stable antiinflammatory prostaglandin (PG) Δ 12 ‐PGJ 2 . Furthermore, using biochemical, genetic, and molecular modeling studies, we show that Δ 12 ‐PGJ 2 covalently modifies a key cysteine residue in the HAT domain of KAT3B, thus inhibiting its activity. Se supplementation resulted in a similar decrease in histone acetylation when used in an HIV‐infection model. These studies suggest the ability of Se in epigenetic modulation of gene expression via an intriguing mechanism that involves endogenous fatty acid metabolites. NIH DK 077152