Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture.
Topological domains are key architectural building blocks of chromosomes, but their functional importance and evolutionary dynamics are not well defined. We performed comparative high-throughput chromosome conformation capture (Hi-C) in four mammals and characterized the conservation and divergence of chromosomal contact insulation and the resulting domain architectures within distantly related genomes. We show that the modular organization of chromosomes is robustly conserved in syntenic regions and that this is compatible with conservation of the binding landscape of the insulator protein CTCF. Specifically, conserved CTCF sites are co-localized with cohesin, are enriched at strong topological domain borders, and bind to DNA motifs with orientations that define the directionality of CTCF's long-range interactions. Conversely, divergent CTCF binding between species is correlated with divergence of internal domain structure, likely driven by local CTCF binding sequence changes, demonstrating how genome evolution can be linked to a continuous flux of local conformation changes. We also show that large-scale domains are reorganized during genome evolution as intact modules.
Research Department of Cancer Biology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Matteo
M
Vietri Rudan
Research Department of Cancer Biology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Christopher
C
Barrington
Research Department of Cancer Biology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Stephen
S
Henderson
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Christina
C
Ernst
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Duncan T
DT
Odom
Department of Computer Science and Applied Mathematics, Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
Amos
A
Tanay
Research Department of Cancer Biology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK. Electronic address: s.hadjur@ucl.ac.uk.
Suzana
S
Hadjur
D000818:Animals; D001665:Binding Sites; D005075:Biological Evolution; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism; D002875:Chromosomes / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D051379:Mice; D059372:Nucleotide Motifs; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D000097722:Cohesins
D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D012097:Repressor Proteins; D000097722:Cohesins; C000619698:Ctcf protein, mouse