title: Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements.
abstract: Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Telorac
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany Dalhousie University, Halifax, NS B3K 6R8, Canada.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Prykhozhij
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schöne
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.affiliation: CU Systems Medicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Computational Systems Biology, Institut de Biologie de l'Ecole Normale, Supérieure (IBENS), CNRS, Inserm, Ecole Normale Supérieure, PSL Research University, F-75005 Paris, France mthomas@biologie.ens.fr.
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomas-Chollier
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany meijsing@molgen.mpg.de.
authors.forename: Sebastiaan H
authors.initials: SH
authors.lastname: Meijsing
mesh_terms: D001483:Base Sequence / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors