title: Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation.
abstract: The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ∼ 2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as "regulons" to enable spatially proximal genes to be coordinately transcribed in response to hormones.
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain; Genome Biology Group, Centre Nacional d'Anàlisi Genòmica (CNAG), 08028 Barcelona, Spain;
authors.forename: François
authors.initials: F
authors.lastname: Le Dily
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Genome Biology Group, Centre Nacional d'Anàlisi Genòmica (CNAG), 08028 Barcelona, Spain;
authors.forename: Davide
authors.initials: D
authors.lastname: Baù
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;
authors.forename: Andy
authors.initials: A
authors.lastname: Pohl
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;
authors.forename: Guillermo P
authors.initials: GP
authors.lastname: Vicent
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Genome Biology Group, Centre Nacional d'Anàlisi Genòmica (CNAG), 08028 Barcelona, Spain;
authors.forename: François
authors.initials: F
authors.lastname: Serra
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;
authors.forename: Daniel
authors.initials: D
authors.lastname: Soronellas
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain; Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;
authors.forename: Roni H G
authors.initials: RH
authors.lastname: Wright
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ballare
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Filion
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Genome Biology Group, Centre Nacional d'Anàlisi Genòmica (CNAG), 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Marti-Renom
authors.affiliation: Gene Regulacion, Stem Cells, and Cancer Program, Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain; miguel.beato@crg.es mmarti@pcb.ub.cat.
authors.forename: Miguel
authors.initials: M
authors.lastname: Beato
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D011372:Progestins / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D006728:Hormones; D011372:Progestins
keywords: Hi-C; TADs; epigenetic landscape; gene expression; progesterone receptor; three-dimensional structure of the genome; transcriptional regulation