title: Role of the chromatin landscape and sequence in determining cell type-specific genomic glucocorticoid receptor binding and gene regulation.
abstract: The genomic loci bound by the glucocorticoid receptor (GR), a hormone-activated transcription factor, show little overlap between cell types. To study the role of chromatin and sequence in specifying where GR binds, we used Bayesian modeling within the universe of accessible chromatin. Taken together, our results uncovered that although GR preferentially binds accessible chromatin, its binding is biased against accessible chromatin located at promoter regions. This bias can only be explained partially by the presence of fewer GR recognition sequences, arguing for the existence of additional mechanisms that interfere with GR binding at promoters. Therefore, we tested the role of H3K9ac, the chromatin feature with the strongest negative association with GR binding, but found that this correlation does not reflect a causative link. Finally, we find a higher percentage of promoter-proximal GR binding for genes regulated by GR across cell types than for cell type-specific target genes. Given that GR almost exclusively binds accessible chromatin, we propose that cell type-specific regulation by GR preferentially occurs via distal enhancers, whose chromatin accessibility is typically cell type-specific, whereas ubiquitous target gene regulation is more likely to result from binding to promoter regions, which are often accessible regardless of cell type examined.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.|Department of Biostatistics, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Love
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Huska
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Jurk
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schöpflin
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Starick
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schwahn
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Cooper
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
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.
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomas-Chollier
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73 14195, Berlin, Germany.
authors.forename: Sebastiaan H
authors.initials: SH
authors.lastname: Meijsing
mesh_terms: D000818:Animals; D001483:Base Sequence; D001499:Bayes Theorem; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D051379:Mice; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D002843:Chromatin; D011965:Receptors, Glucocorticoid; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor