title: CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation.
abstract: It remains uncertain how the DNA sequence of mammalian genes influences the transcriptional response to extracellular signals. Here, we show that the number of CREB-binding sites (CREs) affects whether the related histone acetyltransferases (HATs) CREB-binding protein (CBP) and p300 are required for endogenous gene transcription. Fibroblasts with both CBP and p300 knocked-out had strongly attenuated histone H4 acetylation at CREB-target genes in response to cyclic-AMP, yet transcription was not uniformly inhibited. Interestingly, dependence on CBP/p300 was often different between reporter plasmids and endogenous genes. Transcription in the absence of CBP/p300 correlated with endogenous genes having more CREs, more bound CREB, and more CRTC2 (a non-HAT coactivator of CREB). Indeed, CRTC2 rescued cAMP-inducible expression for certain genes in CBP/p300 null cells and contributed to the CBP/p300-independent expression of other targets. Thus, endogenous genes with a greater local concentration and diversity of coactivators tend to have more resilient-inducible expression. This model suggests how gene expression patterns could be tuned by altering coactivator availability rather than by changing signal input or transcription factor levels.
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lawryn H
authors.initials: LH
authors.lastname: Kasper
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lerach
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Trushar
authors.initials: T
authors.lastname: Jeevan
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; C504923:Crtc2 protein, mouse; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D051548:Histone Acetyltransferases; C045073:Cre recombinase; D019426:Integrases