title: Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments.
abstract: Chromosome conformation capture approaches have shown that interphase chromatin is partitioned into spatially segregated Mb-sized compartments and sub-Mb-sized topological domains. This compartmentalization is thought to facilitate the matching of genes and regulatory elements, but its precise function and mechanistic basis remain unknown. Cohesin controls chromosome topology to enable DNA repair and chromosome segregation in cycling cells. In addition, cohesin associates with active enhancers and promoters and with CTCF to form long-range interactions important for gene regulation. Although these findings suggest an important role for cohesin in genome organization, this role has not been assessed on a global scale. Unexpectedly, we find that architectural compartments are maintained in noncycling mouse thymocytes after genetic depletion of cohesin in vivo. Cohesin was, however, required for specific long-range interactions within compartments where cohesin-regulated genes reside. Cohesin depletion diminished interactions between cohesin-bound sites, whereas alternative interactions between chromatin features associated with transcriptional activation and repression became more prominent, with corresponding changes in gene expression. Our findings indicate that cohesin-mediated long-range interactions facilitate discrete gene expression states within preexisting chromosomal compartments.
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Vlad C
authors.initials: VC
authors.lastname: Seitan
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Faure
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhan
authors.forename: Rachel Patton
authors.initials: RP
authors.lastname: McCord
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Lajoie
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ing-Simmons
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Luca
authors.initials: L
authors.lastname: Giorgetti
authors.forename: Edith
authors.initials: E
authors.lastname: Heard
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000502:physiology*; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D033481:Chromosomes, Mammalian; D004268:DNA-Binding Proteins; D018628:Gene Dosage; D005786:Gene Expression Regulation; D016678:Genome; D016014:Linear Models; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism*; D060168:Thymocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097722:Cohesins; C000619698:Ctcf protein, mouse; C546088:Nipbl protein, mouse; C465862:Rad21 protein, mouse