Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers

  1. Jérôme Eeckhoute1,2,3,8,9
  1. 1 Université de Rennes 1, 35065 Rennes, France;
  2. 2 CNRS, UMR 6026, équipe SPARTE, labellisée “Ligue nationale contre le cancer,” Campus de Beaulieu, 35042 Rennes, France;
  3. 3 Université européenne de Bretagne, 35000 Rennes, France;
  4. 4 CNRS, UMR 6026, équipe RED, Campus de Beaulieu, 35042 Rennes, France;
  5. 5 Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
  6. 6 Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA
    1. 7 These authors contributed equally to this work.

    • 8 Present address: INSERM UMR1011-Bâtiment J&K, Univ. Lille-Nord de France, Faculté de Médecine de Lille-Pôle Recherche, Boulevard du Professeur Leclerc, 59045 Lille cedex, France.

    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.

    Footnotes

    • 9 Corresponding authors.

      E-mail gilles.salbert{at}univ-rennes1.fr.

      E-mail jerome.eeckhoute{at}inserm.fr.

    • [Supplemental material is available for this article. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession no. GSE21513.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.111534.110.

    • Received July 3, 2010.
    • Accepted January 5, 2011.
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