title: Cohesin-mediated interactions organize chromosomal domain architecture.
abstract: To ensure proper gene regulation within constrained nuclear space, chromosomes facilitate access to transcribed regions, while compactly packaging all other information. Recent studies revealed that chromosomes are organized into megabase-scale domains that demarcate active and inactive genetic elements, suggesting that compartmentalization is important for genome function. Here, we show that very specific long-range interactions are anchored by cohesin/CTCF sites, but not cohesin-only or CTCF-only sites, to form a hierarchy of chromosomal loops. These loops demarcate topological domains and form intricate internal structures within them. Post-mitotic nuclei deficient for functional cohesin exhibit global architectural changes associated with loss of cohesin/CTCF contacts and relaxation of topological domains. Transcriptional analysis shows that this cohesin-dependent perturbation of domain organization leads to widespread gene deregulation of both cohesin-bound and non-bound genes. Our data thereby support a role for cohesin in the global organization of domain structure and suggest that domains function to stabilize the transcriptional programmes within them.
authors.affiliation: Research Department of Cancer Biology, Cancer Institute, University College London, London, UK.
authors.forename: Sevil
authors.initials: S
authors.lastname: Sofueva
authors.forename: Eitan
authors.initials: E
authors.lastname: Yaffe
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Chan
authors.forename: Dimitra
authors.initials: D
authors.lastname: Georgopoulou
authors.forename: Matteo
authors.initials: M
authors.lastname: Vietri Rudan
authors.forename: Hegias
authors.initials: H
authors.lastname: Mira-Bontenbal
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Amos
authors.initials: A
authors.lastname: Tanay
authors.forename: Suzana
authors.initials: S
authors.lastname: Hadjur
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002875:Chromosomes / Q000737:chemistry* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D051379:Mice; D008938:Mitosis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D000097722:Cohesins; C000619698:Ctcf protein, mouse; C465862:Rad21 protein, mouse