title: Nucleosome-driven transcription factor binding and gene regulation.
abstract: Elucidating the global function of a transcription factor implies the identification of its target genes and genomic binding sites. The role of chromatin in this context is unclear, but the dominant view is that factors bind preferentially to nucleosome-depleted regions identified as DNaseI-hypersensitive sites (DHS). Here we show by ChIP, MNase, and DNaseI assays followed by deep sequencing that the progesterone receptor (PR) requires nucleosomes for optimal binding and function. In breast cancer cells treated with progestins, we identified 25,000 PR binding sites (PRbs). The majority of these sites encompassed several copies of the hexanucleotide TGTYCY, which is highly abundant in the genome. We found that functional PRbs accumulate around progesterone-induced genes, mainly in enhancers. Most of these sites overlap with DHS but exhibit high nucleosome occupancy. Progestin stimulation results in remodeling of these nucleosomes with displacement of histones H1 and H2A/H2B dimers. Our results strongly suggest that nucleosomes are crucial for PR binding and hormonal gene regulation.
authors.affiliation: Gene Regulation Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ballaré
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.forename: Laura
authors.initials: L
authors.lastname: Gaveglia
authors.forename: Sonja
authors.initials: S
authors.lastname: Althammer
authors.forename: Juan
authors.initials: J
authors.lastname: González-Vallinas
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyras
authors.forename: Francois
authors.initials: F
authors.lastname: Le Dily
authors.forename: Roser
authors.initials: R
authors.lastname: Zaurin
authors.forename: Daniel
authors.initials: D
authors.lastname: Soronellas
authors.forename: Guillermo P
authors.initials: GP
authors.lastname: Vicent
authors.forename: Miguel
authors.initials: M
authors.lastname: Beato
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D016384:Consensus Sequence; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D009707:Nucleosomes / Q000378:metabolism* / Q000502:physiology; D011372:Progestins / Q000502:physiology; D011485:Protein Binding; D011980:Receptors, Progesterone / Q000378:metabolism*; D020218:Response Elements; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D006657:Histones; D009707:Nucleosomes; D011372:Progestins; D011980:Receptors, Progesterone; D014157:Transcription Factors