Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages
Xuefen Chen1, Iros Barozzi, Alberto Termanini
1Italian Institute of Technology at European School of Molecular Medicine, 20139 Milan, Italy.
Insights
Histone deacetylase 3 (HDAC3) is crucial for macrophage inflammatory responses. Its deficiency impairs the inflammatory gene expression program, partly by affecting IFN-β production, highlighting HDAC3
Area of Science:
- Immunology
- Molecular Biology
- Epigenetics
Background:
- Histone deacetylases (HDACs) are epigenetic regulators implicated in inflammatory processes.
- Pan-HDAC inhibitors exhibit anti-inflammatory effects, but the roles of individual HDACs remain unclear.
- Understanding specific HDAC contributions is vital for targeted anti-inflammatory therapies.
Purpose of the Study:
- To elucidate the specific role of Histone deacetylase 3 (HDAC3) in regulating the inflammatory gene expression program in macrophages.
- To investigate the molecular mechanisms by which HDAC3 controls inflammatory gene activation.
Main Methods:
- Utilized an integrated genomic approach to analyze gene expression in Hdac3-deficient macrophages.
- Stimulated macrophages with lipopolysaccharide (LPS) to assess inflammatory responses.
- Investigated the role of Interferon-beta (IFN-β) and Stat1 signaling.
- Examined the impact of HDAC3 on nuclear receptor targets and gene acetylation.
- Assessed the effect of inhibiting prostaglandin endoperoxide synthase 1 (Ptgs1/Cox-1).
Main Results:
- Hdac3-deficient macrophages exhibited impaired activation of nearly half of the inflammatory gene expression program upon LPS stimulation.
- A significant defect was observed in both basal and LPS-inducible expression of IFN-β, impacting Stat1-dependent gene expression.
- Loss of HDAC3-mediated repression of nuclear receptors led to widespread gene hyperacetylation and derepression.
- Upregulation of Ptgs1 (Cox-1) was identified as a contributing factor to the observed phenotype, with its inhibition partially rescuing the IFN-β activation defect.
Conclusions:
- HDAC3 plays a central role in orchestrating the inflammatory gene expression program in macrophages.
- HDAC3 regulates inflammatory responses through mechanisms involving IFN-β production and Stat1 signaling.
- These findings suggest that selective HDAC3 inhibitors could be valuable therapeutic agents for inflammatory diseases.
Abstract:
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.
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