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

By Benjamin D. Pope, T. Ryba, Vishnu Dileep, Feng Yue, Wei-Sheng Wu, Olgert Denas, Daniel L. Vera, Yanli Wang, R. Hansen, T. Canfield and 11 more. Nature, 2014

841 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bbd50a4fc71c5f22fd38381aaf5a5585eccf6463

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Citations in the corpus

YY1 Is a Structural Regulator of Enhancer-Promoter Loops (2017, neutral): “…et al., 1993); Lin et al. (2010); Lobanenkov et al. (1990); Mendenhall et al. (2010); Moore et al. (2012); Natesan and Gilman (1993); Nora et al. (2016); Pope et al. (2014); Seto et al. (1991); Stadler et al. (2011); Wang et al. (2012); Wu et al. (2007); Xu et al. (2007); Yusufzai et al. (2004).”
Chromatin-state discovery and genome annotation with ChromHMM (2017, methodology): “…ChromHMM has been used for understanding long-range chromatin interactions 21 , nascent transcripts 22 , cellular reprogramming 14,23 , topologically associated domains 24 , transcription-factor binding preferences 1,25 , and regulatory motif disruptions in massively parallel reporter assays 26 .”
Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM) (2017, neutral): “These include the identification of large self-associating regions called topologically associating domains (TADs)3,5, the elucidation of links between spatial positioning and the DNA replication program11,12 and the structural dissection of mitotic chromatin13,14.”
Regulation of disease-associated gene expression in the 3D genome (2016, positive): “TAD boundaries tend to separate domains with dis tinct chromatin signatures, distinct gene activity and distinct replication timing 57–59, 73 , 74 , whereas CTCF and cohesin are important players in the establishment of the architectural loops that partition chromosomes into structural domains.”