title: Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation.
abstract: Mammalian chromosomes fold into arrays of megabase-sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher-order organization remains elusive. Here, we investigate TAD higher-order interactions with Hi-C through neuronal differentiation and show that they form a hierarchy of domains-within-domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree-like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.
authors.affiliation: Department of Biochemistry, Goodman Cancer Centre, McGill University, Montréal, QC, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Fraser
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany Genome Function Group, MRC Clinical Sciences Centre, Imperial College London Hammersmith Hospital Campus, London, UK.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Ferrai
authors.affiliation: Dipartimento di Fisica, Università di Napoli Federico II INFN Napoli CNR-SPIN Complesso Universitario di Monte Sant'Angelo, Naples, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Chiariello
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin-Buch, 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, Berlin-Buch, Germany.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rito
authors.affiliation: Dipartimento di Fisica, Università di Napoli Federico II INFN Napoli CNR-SPIN Complesso Universitario di Monte Sant'Angelo, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laudanno
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbieri
authors.affiliation: MRC Human Genetics Unit, MRC IGMM University of Edinburgh, Edinburgh, UK.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Moore
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Dorothee C A
authors.initials: DC
authors.lastname: Kraemer
authors.affiliation: MRC Human Genetics Unit, MRC IGMM University of Edinburgh, Edinburgh, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Aitken
authors.affiliation: Genome Function Group, MRC Clinical Sciences Centre, Imperial College London Hammersmith Hospital Campus, London, 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, Berlin-Buch, Germany Genome Function Group, MRC Clinical Sciences Centre, Imperial College London Hammersmith Hospital Campus, London, UK.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Morris
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako Saitama, Japan Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama Kanagawa, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako Saitama, Japan Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama Kanagawa, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: Stem Cell Neurogenesis Group, MRC Clinical Sciences Centre, Imperial College London Hammersmith Hospital Campus, London, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: Jaeger
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako Saitama, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama Kanagawa, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama Kanagawa, Japan.
authors.forename: Alistair R R
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: MRC Human Genetics Unit, MRC IGMM University of Edinburgh, Edinburgh, UK colin.semple@igmm.ed.ac.uk josee.dostie@mcgill.ca ana.pombo@mdc-berlin.de mario.nicodemi@na.infn.it.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Semple
authors.affiliation: Department of Biochemistry, Goodman Cancer Centre, McGill University, Montréal, QC, Canada colin.semple@igmm.ed.ac.uk josee.dostie@mcgill.ca ana.pombo@mdc-berlin.de mario.nicodemi@na.infn.it.
authors.forename: Josée
authors.initials: J
authors.lastname: Dostie
authors.affiliation: Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany Genome Function Group, MRC Clinical Sciences Centre, Imperial College London Hammersmith Hospital Campus, London, UK colin.semple@igmm.ed.ac.uk josee.dostie@mcgill.ca ana.pombo@mdc-berlin.de mario.nicodemi@na.infn.it.
authors.forename: Ana
authors.initials: A
authors.lastname: Pombo
authors.affiliation: Dipartimento di Fisica, Università di Napoli Federico II INFN Napoli CNR-SPIN Complesso Universitario di Monte Sant'Angelo, Naples, Italy colin.semple@igmm.ed.ac.uk josee.dostie@mcgill.ca ana.pombo@mdc-berlin.de mario.nicodemi@na.infn.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Nicodemi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry*; D042002:Chromatin Assembly and Disassembly; D002875:Chromosomes / Q000737:chemistry*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin
keywords: chromatin contacts; chromosome architecture; epigenetics; gene expression; polymer modelling