title: Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling.
abstract: Forkhead box O (FOXO) transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into the mechanisms of FOXO-regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows that FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture.
authors: Department of Molecular Cancer Research, University Medical Centre, Utrecht, The Netherlands.
authors: Astrid
authors: A
authors: Eijkelenboom
authors: Michal
authors: M
authors: Mokry
authors: Elzo
authors: E
authors: de Wit
authors: Lydia M
authors: LM
authors: Smits
authors: Paulien E
authors: PE
authors: Polderman
authors: Miranda H
authors: MH
authors: van Triest
authors: Ruben
authors: R
authors: van Boxtel
authors: Almut
authors: A
authors: Schulze
authors: Wouter
authors: W
authors: de Laat
authors: Edwin
authors: E
authors: Cuppen
authors: Boudewijn M T
authors: BM
authors: Burgering
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012319:RNA Polymerase II