Deacetylase activity is required for cAMP activation of a subset of CREB target genes.
Many hormones activate transcription by raising the level of cAMP within cells. In one well studied pathway, cAMP induces protein kinase A to phosphorylate the transcription factor CREB, which binds to a consensus sequence, the cAMP-regulated enhancer, found in many target genes. A generally accepted model suggests that phosphorylated CREB recruits the histone acetyltransferase CBP to activate transcription. In contrast, histone deacetylases have been linked to the cessation of CREB-dependent transcription. Here we tested this model in the regulation of endogenous CREB target genes. We used a constitutively active CREB mutant and microarray analysis to identify target genes in PC12 cells. We then tested the role of histone deacetylase activity in cAMP activation of four of these genes (c-FOS, ICER, NOR-1, and NUR77) by treating cells with the histone deacetylase inhibitor trichostatin A. Consistent with the generally accepted model, trichostatin A enhanced activation of c-FOS and NUR77 by cAMP. Surprisingly, trichostatin A blocked activation of ICER and NOR-1. The block of ICER and NOR-1 activation persisted in the presence of cycloheximide, indicating that the trichostatin A effect did not depend on new protein synthesis. This unexpected role of histone deacetylases in transcriptional activation of certain endogenous CREB target genes was not apparent in transfected reporter genes. Chromatin immunoprecipitation analysis indicated that the differential roles of histone deacetylases in activating or repressing CREB target genes was manifested at the level of preinitiation complex recruitment. These data indicate that histone deacetylases differentially regulate CREB target genes by contributing to either activation or cessation of transcription.
Fass
Daniel M
DM
Vollum Institute L474, Oregon Health and Science University, Portland, Oregon 97239, USA.
Butler
Jennifer E F
JE
Goodman
Richard H
RH
D000123:Acetyltransferases / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005656:Fungal Proteins; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D064430:NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; D016716:PC12 Cells; D010766:Phosphorylation; D011233:Precipitin Tests; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D002843:Chromatin; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D006877:Hydroxamic Acids; D011500:Protein Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D051786:Cyclic AMP Response Element Modulator; C012589:trichostatin A; D003513:Cycloheximide; D000242:Cyclic AMP; D000429:Alcohol Oxidoreductases; D064430:NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; C062609:norsolorinic acid ketoreductase; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases