Topologically associating domains are stable units of replication-timing regulation

Abstract

SummaryEukaryotic chromosomes replicate in a temporal order known as the replication-timing program1. During mammalian development, at least half the genome changes replication timing, primarily in units of 400–800 kb (“replication domains”; RDs), 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 strongly with open and closed chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, lamina-associated domains (LADs)4,5,8,9. Recent Hi-C mapping has unveiled a substructure of topologically-associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to RDs8,10. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale11,12. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure8,9,13. Here, we localize boundaries of RDs 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, RD boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure RD 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 with developmentally stable chromosome domains and offer a unified model for large-scale chromosome structure and function.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

“…Median coverage of whole-exome sequenced tumour samples was 157-fold (range 43-469×) and for control samples (blood DNA) 146-fold (range 80-222×). In addition, whole genome libraries (before the exome hybridization step) were sequenced three lanes each in paired end 105bp mode on the HiSeq2000, as described earlier by Jones et al 15 .…”

“…We hypothesized that this core model would be further specified by additional TFs that delineate the transcriptional differences between molecular subgroups of ependymoma. An integrative analysis was performed to assess subgroup specific enhancers, the expression of their target genes within local topological associated domains 15 , and the enrichment of subgroup specific TF binding motifs at these subgroup specific enhancer loci. Using this approach, we modelled regulatory circuitry maps of each molecular subgroup of ependymoma, as defined by distinct sets of TFs, potentially utilized in order to establish and/or maintain ependymoma subgroup identity (Fig.…”

Higher order chromatin structures are taking shape

“…The boundaries between domains act as insulators and correspond to insulators between enhancer elements and promoters that have been identified more than twenty years ago [18]. TAD boundaries also correspond to the limits of γH2A.X spreading upon DNA damage [19] and to replication domains [20]. These new findings suggest that chromosomal domains are functional compartments of chromosomes within which the productive contacts between genomic elements are strongly favored.…”

Nonreplicative functions of the origin recognition complex

“…In particular, the regions of early replication coincide with the TADs of euchromatin, whereas the TADs of heterochromatin contain the late replicating regions and timing transition regions [96]. Thus, the locations of TADs determine the difference between the early- and the late-replicating regions.…”