Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages

Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic appr...

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Vydané v:Proceedings of the National Academy of Sciences - PNAS Ročník 109; číslo 42; s. E2865
Hlavní autori: Chen, Xuefen, Barozzi, Iros, Termanini, Alberto, Prosperini, Elena, Recchiuti, Antonio, Dalli, Jesmond, Mietton, Flore, Matteoli, Gianluca, Hiebert, Scott, Natoli, Gioacchino
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 16.10.2012
Predmet:
Animals
Base Sequence
Chromatin Immunoprecipitation
Cyclooxygenase 1 - metabolism
Cytokines - analysis
DNA Primers - genetics
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Gene Expression Regulation - genetics
Genomics
Histone Deacetylases - deficiency
Histone Deacetylases - metabolism
Macrophages - metabolism
Membrane Proteins - metabolism
Mice
Mice, Transgenic
Molecular Sequence Data
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA
ISSN:1091-6490, 1091-6490
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Shrnutí:Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and associated gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chemical inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.
Bibliografia:ObjectType-Article-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1121131109