title: Hormone-responsive enhancer-activity maps reveal predictive motifs, indirect repression, and targeting of closed chromatin.
abstract: Steroid hormones act as important developmental switches, and their nuclear receptors regulate many genes. However, few hormone-dependent enhancers have been characterized, and important aspects of their sequence architecture, cell-type-specific activating and repressing functions, or the regulatory roles of their chromatin structure have remained unclear. We used STARR-seq, a recently developed enhancer-screening assay, and ecdysone signaling in two different Drosophila cell types to derive genome-wide hormone-dependent enhancer-activity maps. We demonstrate that enhancer activation depends on cis-regulatory motif combinations that differ between cell types and can predict cell-type-specific ecdysone targeting. Activated enhancers are often not accessible prior to induction. Enhancer repression following hormone treatment seems independent of receptor motifs and receptor binding to the enhancer, as we show using ChIP-seq, but appears to rely on motifs for other factors, including Eip74. Our strategy is applicable to study signal-dependent enhancers for different pathways and across organisms.
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Daria
authors.initials: D
authors.lastname: Shlyueva
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stelzer
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gerlach
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: J Omar
authors.initials: JO
authors.lastname: Yáñez-Cuna
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Rath
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Łukasz M
authors.initials: ŁM
authors.lastname: Boryń
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Cosmas D
authors.initials: CD
authors.lastname: Arnold
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria. Electronic address: stark@starklab.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stark
mesh_terms: D000818:Animals; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D019295:Computational Biology; D030541:Databases, Genetic; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004440:Ecdysone / Q000494:pharmacology*; D004742:Enhancer Elements, Genetic / Q000187:drug effects*; D063185:Epigenetic Repression / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D059372:Nucleotide Motifs / Q000187:drug effects*; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D060388:Support Vector Machine; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: D004440:Ecdysone