title: FOXO3 selectively amplifies enhancer activity to establish target gene regulation.
abstract: Forkhead box O (FOXO) transcription factors regulate diverse cellular processes, affecting tumorigenesis, metabolism, stem cell maintenance, and lifespan. We show that FOXO3 transcription regulation mainly proceeds through the most active subset of enhancers. In addition to the general distinction between "open" and "closed" chromatin, we show that the level of activity marks (H3K27ac, RNAPII, enhancer RNAs) of these open chromatin regions prior to FOXO3 activation largely determines FOXO3 DNA binding. Consequently, FOXO3 amplifies the levels of these activity marks and their absolute rather than relative changes associate best with FOXO3 target gene regulation. The importance of preexisting chromatin state in directing FOXO3 gene regulation, as shown here, provides a mechanism whereby FOXO3 can regulate cell-specific homeostasis. Genetic variation is reported to affect these chromatin signatures in a quantitative manner, and, in agreement, we observe a correlation between cancer-associated genetic variations and the amplitude of FOXO3 enhancer binding.
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Astrid
authors.initials: A
authors.lastname: Eijkelenboom
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Smits
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands. Electronic address: b.m.t.burgering@umcutrecht.nl.
authors.forename: Boudewijn M T
authors.initials: BM
authors.lastname: Burgering
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006657:Histones; D012319:RNA Polymerase II