Abstract
Class I histone deacetylases (HDACs) are ubiquitous enzymes that repress gene expression by deacetylating histone tails and promoting chromatin compaction. Pro-inflammatory agents activate programmes of gene expression through transcription factors such as nuclear factor-kappaB (NF-kappaB), even in the context of ubiquitous HDAC activity. How this is accomplished remains unknown. We found that cells treated with the pro-inflammatory cytokine tumour necrosis factor-alpha rapidly and substantially reduced HDAC1 protein levels without affecting other class I HDACs. In addition, HDAC1 depletion occurred through protein degradation, required IKK2 activity and resulted in increased transcription from both NF-kappaB-associated and unassociated gene promoters. Our study suggests that the activation of programmes of gene expression by pro-inflammatory agents requires global changes in specific critical epigenetic regulators such as HDAC1.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Gene Expression Regulation*
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Histone Deacetylase 1
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Histone Deacetylases / classification
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism*
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Interleukin-1 / metabolism
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Lipopolysaccharides / metabolism
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Membrane Glycoproteins / metabolism
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Mice
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Apoptosis Regulatory Proteins
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Interleukin-1
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Lipopolysaccharides
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Membrane Glycoproteins
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RNA, Small Interfering
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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I-kappa B Kinase
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HDAC1 protein, human
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Histone Deacetylase 1
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Histone Deacetylases