TY - JOUR
T1 - Topologically associating domains are stable units of replication-timing regulation
AU - Pope, Benjamin D.
AU - Ryba, Tyrone
AU - Dileep, Vishnu
AU - Yue, Feng
AU - Wu, Weisheng
AU - Denas, Olgert
AU - Vera, Daniel L.
AU - Wang, Yanli
AU - Hansen, R. Scott
AU - Canfield, Theresa K.
AU - Thurman, Robert E.
AU - Cheng, Yong
AU - Gülsoy, Günhan
AU - Dennis, Jonathan H.
AU - Snyder, Michael P.
AU - Stamatoyannopoulos, John A.
AU - Taylor, James
AU - Hardison, Ross C.
AU - Kahveci, Tamer
AU - Ren, Bing
AU - Gilbert, David M.
N1 - Funding Information:
Acknowledgements We thank A. Laugesen, G. Andersen and K. Helin for providing Suz12 controlandknockout naive mESC lines.WethankF.Ay,M.Libbrecht,W.S. Noble, E. Besnard, J. M. LeMaitre, C. Cayrou, M. Mechali and J. Dekker for helpful discussions. This research was supported by NIH grants GM083337 and GM085354 to D.M.G., HG005602 to M.P.S., HG005573 and DK065806 to R.C.H., and HG003991 to B.R. B.D.P. is supported by the National Cancer Institute of the National Institutes of Health under award number F31CA165863.
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/11/20
Y1 - 2014/11/20
N2 - Eukaryotic chromosomesreplicate in a temporal order knownas the replication-timing program1. Inmammals, replication timing is celltype-specificwith at least half thegenomeswitching replicationtiming during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements2-7. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs)4,5,8,9. Recent Hi-Cmapping hasunveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains8,10. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale11,12.Moreover, attempts to reconcileTADs andLADs to replication-timing data have not revealed a common, underlying domain structure8,9,13. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions andmap their positions in 18 human and 13mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacentTADsthat replicate at similar times obscure replication domainboundaries, largely accounting for thepreviously reported lack of alignment. Moreover, cell-type-specific replication timing ofTADspartitions the genome into twolarge-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timingwith developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.
AB - Eukaryotic chromosomesreplicate in a temporal order knownas the replication-timing program1. Inmammals, replication timing is celltype-specificwith at least half thegenomeswitching replicationtiming during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements2-7. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs)4,5,8,9. Recent Hi-Cmapping hasunveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains8,10. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale11,12.Moreover, attempts to reconcileTADs andLADs to replication-timing data have not revealed a common, underlying domain structure8,9,13. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions andmap their positions in 18 human and 13mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacentTADsthat replicate at similar times obscure replication domainboundaries, largely accounting for thepreviously reported lack of alignment. Moreover, cell-type-specific replication timing ofTADspartitions the genome into twolarge-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timingwith developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.
UR - http://www.scopus.com/inward/record.url?scp=84911478490&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84911478490&partnerID=8YFLogxK
U2 - 10.1038/nature13986
DO - 10.1038/nature13986
M3 - Article
C2 - 25409831
AN - SCOPUS:84911478490
SN - 0028-0836
VL - 515
SP - 402
EP - 405
JO - Nature
JF - Nature
IS - 7527
ER -