Topologically associating domains are stable units of replication-timing regulation
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.
TAD Structures Influence Genetic Function 1
Human cell in anaphaseThe structures of TADs correlate with many kinds of activity in different regions of chromosomes. This correlation includes modification of histones, specific genes use and copying DNA.
Using TADs, chromatin forms two discrete areas—one active DNA and the other mostly inactive DNA. In facultative type chromatin, the two regions shift during fetal development. With constitutive, the size of the two regions stays the same. Instead they have active loops combining enhancers and promoters.
An important example of how TADs influence gene function is found with the Hox genes that are used in sequence during fetal development related to the positions of the body from the front to the back. H3 trimethylation of lysine 4 marks the active regions and a different methylation marks the inactive places. As the genes are used during fetal development, the marks change. The 3D chromatin changes shape with the active TAD region enlarging and the inactive region shrinking. In this way the code and the 3D structure work together; it is not clear which is directing or following.
more reading: Chromatin-Driven Behavior of Topologically Associating Domains