title: Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers.
abstract: Transcription factors (TFs) bind specifically to discrete regions of mammalian genomes called cis-regulatory elements. Among those are enhancers, which play key roles in regulation of gene expression during development and differentiation. Despite the recognized central regulatory role exerted by chromatin in control of TF functions, much remains to be learned regarding the chromatin structure of enhancers and how it is established. Here, we have analyzed on a genomic-scale enhancers that recruit FOXA1, a pioneer transcription factor that triggers transcriptional competency of these cis-regulatory sites. Importantly, we found that FOXA1 binds to genomic regions showing local DNA hypomethylation and that its cell-type-specific recruitment to chromatin is linked to differential DNA methylation levels of its binding sites. Using neural differentiation as a model, we showed that induction of FOXA1 expression and its subsequent recruitment to enhancers is associated with DNA demethylation. Concomitantly, histone H3 lysine 4 methylation is induced at these enhancers. These epigenetic changes may both stabilize FOXA1 binding and allow for subsequent recruitment of transcriptional regulatory effectors. Interestingly, when cloned into reporter constructs, FOXA1-dependent enhancers were able to recapitulate their cell type specificity. However, their activities were inhibited by DNA methylation. Hence, these enhancers are intrinsic cell-type-specific regulatory regions of which activities have to be potentiated by FOXA1 through induction of an epigenetic switch that includes notably DNA demethylation.
authors.affiliation: Université de Rennes 1, Rennes, France.
authors.forename: Aurélien A
authors.initials: AA
authors.lastname: Sérandour
authors.forename: Stéphane
authors.initials: S
authors.lastname: Avner
authors.forename: Frédéric
authors.initials: F
authors.lastname: Percevault
authors.forename: Florence
authors.initials: F
authors.lastname: Demay
authors.forename: Maud
authors.initials: M
authors.lastname: Bizot
authors.forename: Céline
authors.initials: C
authors.lastname: Lucchetti-Miganeh
authors.forename: Frédérique
authors.initials: F
authors.lastname: Barloy-Hubler
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.forename: Raphaël
authors.initials: R
authors.lastname: Métivier
authors.forename: Gilles
authors.initials: G
authors.lastname: Salbert
authors.forename: Jérôme
authors.initials: J
authors.lastname: Eeckhoute
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D057890:Epigenomics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009474:Neurons / Q000166:cytology / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones