title: Histone deacetylase activity modulates alternative splicing.
abstract: There is increasing evidence to suggest that splicing decisions are largely made when the nascent RNA is still associated with chromatin. Here we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection. Using splicing-sensitive microarrays, we identified ∼700 genes whose splicing was altered after HDAC inhibition. We provided evidence that HDAC inhibition induced histone H4 acetylation and increased RNA Polymerase II (Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduced co-transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. We further showed that the depletion of HDAC1 had similar effect on fibronectin alternative splicing as global HDAC inhibition. Importantly, this effect was reversed upon expression of mouse HDAC1 but not a catalytically inactive mutant. These results provide a molecular insight into a complex modulation of splicing by HDACs and chromatin modifications.
authors.affiliation: Department of RNA Biology, Institute of Molecular Genetics AS CR, Prague, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Hnilicová
authors.forename: Samira
authors.initials: S
authors.lastname: Hozeifi
authors.forename: Eva
authors.initials: E
authors.lastname: Dušková
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Icha
authors.forename: Tereza
authors.initials: T
authors.lastname: Tománková
authors.forename: David
authors.initials: D
authors.lastname: Staněk
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D014162:Transfection
chemical_list: D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases