title: Complex multi-enhancer contacts captured by genome architecture mapping.
abstract: The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.|Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.|Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beagrie
authors.affiliation: Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant'Angelo, 80126 Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Scialdone
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schueler
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.
authors.forename: Dorothee C A
authors.initials: DC
authors.lastname: Kraemer
authors.affiliation: Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Mita
authors.initials: M
authors.lastname: Chotalia
authors.affiliation: Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Sheila Q
authors.initials: SQ
authors.lastname: Xie
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.|Berlin Institute of Health (BIH), Berlin 10117, Germany.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbieri
authors.affiliation: Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: de Santiago
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.|Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Liron-Mark
authors.initials: LM
authors.lastname: Lavitas
authors.affiliation: Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Branco
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec H3G 1Y6, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Fraser
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec H3G 1Y6, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Dostie
authors.affiliation: Genomics Laboratory, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Game
authors.affiliation: Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Niall
authors.initials: N
authors.lastname: Dillon
authors.affiliation: Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Cambridge CB2 0XZ, UK.
authors.forename: Paul A W
authors.initials: PA
authors.lastname: Edwards
authors.affiliation: Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant'Angelo, 80126 Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Nicodemi
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.|Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.|Berlin Institute of Health (BIH), Berlin 10117, Germany.|Institute for Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Pombo
mesh_terms: D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002874:Chromosome Mapping; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D016678:Genome / Q000235:genetics*; D008297:Male; D051379:Mice; D008957:Models, Genetic; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002843:Chromatin