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Nature. 2014 Nov 20;515(7527):402-5. doi: 10.1038/nature13986.

Topologically associating domains are stable units of replication-timing regulation.

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Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306, USA.
Division of Natural Sciences, 5800 Bay Shore Road, New College of Florida, Sarasota, Florida 34243, USA.
1] Department of Biochemistry and Molecular Biology, School of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA [2] Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA.
Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, California 94305, USA.
Computer and Information Sciences and Engineering, University of Florida, Gainesville, Florida 32611, USA.
Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA.


Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing 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 rearrangements. 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). Recent Hi-C mapping has unveiled 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 domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-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 timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.

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