Tumour necrosis factor-alpha depletes histone deacetylase 1 protein through IKK2.
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.
Vashisht Gopal
Y N
YN
Department of Molecular and Cellular Oncology, Unit 079, UT M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Arora
Tarandeep S
TS
Van Dyke
Michael W
MW
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051550:I-kappa B Kinase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases