Activation of the mouse histone deacetylase 1 gene by cooperative histone phosphorylation and acetylation.
Histone deacetylase 1 (HDAC1) is a major regulator of chromatin structure and gene expression. Tight control of HDAC1 expression is essential for normal cell cycle progression of mammalian cells. HDAC1 mRNA levels are regulated by growth factors and by changes in intracellular deacetylase activity levels. Stimulation of the mitogen-activated protein kinase cascade by anisomycin or growth factors, together with inhibition of deacetylases by trichostatin A (TSA), leads to stable histone H3 phosphoacetylation and strongly induced HDAC1 expression. In contrast, activation of the nucleosomal response by anisomycin alone results only in transient phosphoacetylation of histone H3 without affecting HDAC1 mRNA levels. The transcriptional induction of the HDAC1 gene by anisomycin and TSA is efficiently blocked by H89, an inhibitor of the nucleosomal response. Detailed studies of the kinetics of histone acetylation and phosphorylation show that the two modifications are synergistic and essential for induced HDAC1 transcription. Activation of the HDAC1 gene by anisomycin together with TSA or by growth factors is accompanied by phosphoacetylation of HDAC1 promoter-associated histone H3. Our results present evidence for a precise regulatory mechanism which allows induction of the HDAC1 gene in response to proliferation signals and modulation of HDAC1 expression dependent on intracellular deacetylase levels.
Hauser
Christoph
C
Institute of Medical Biochemistry, Department of Molecular Biology, University of Vienna, Vienna Biocenter, A-1030 Vienna, Austria.
Schuettengruber
Bernd
B
Bartl
Stefan
S
Lagger
Gerda
G
Seiser
Christian
C
D016475:3T3 Cells; D000107:Acetylation; D000818:Animals; D000841:Anisomycin / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D006133:Growth Substances / Q000378:metabolism; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D004791:Enzyme Inhibitors; D006133:Growth Substances; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009707:Nucleosomes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; C012589:trichostatin A; D000841:Anisomycin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases