title: Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements.
abstract: The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. Contradicting results have been reported to date, with little consensus about the dynamics of nuclear organization and the features of the contact loci. In this study, we investigated the properties and dynamics of genomic loci that are in contact with glucocorticoid receptor (GR)-responsive loci. We took a systematic approach, combining genome-wide interaction profiling by the chromosome conformation capture on chip (4C) technology with expression, protein occupancy, and chromatin accessibility profiles. This approach allowed a comprehensive analysis of how distinct features of the linear genome are organized in the three-dimensional nuclear space in the context of rapid gene regulation. We found that the transcriptional response to GR occurs without dramatic nuclear reorganization. Moreover, contrary to the view of transcription-driven organization, even genes with opposite transcriptional responses colocalize. Regions contacting GR-regulated genes are not particularly enriched for GR-regulated loci or for any functional group of genes, suggesting that these subnuclear environments are not organized to respond to a specific factor. The contact regions are, however, highly enriched for DNase I-hypersensitive sites that comprehensively mark cell-type-specific regulatory sites. These findings indicate that the nucleus is pre-organized in a conformation allowing rapid transcriptional reprogramming, and this organization is significantly correlated with cell-type-specific chromatin sites accessible to regulatory factors. Numerous open chromatin loci may be arranged in nuclear domains that are poised to respond to diverse signals in general and to permit efficient gene regulation.
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA.
authors.forename: Ofir
authors.initials: O
authors.lastname: Hakim
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.forename: Ty C
authors.initials: TC
authors.lastname: Voss
authors.forename: Erik
authors.initials: E
authors.lastname: Splinter
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sabo
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000737:chemistry / Q000648:ultrastructure; D005786:Gene Expression Regulation; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D011506:Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone