Defining the separation landscape of topological domains for decoding consensus domain organization of 3D genome

Summary Topologically associating domains (TADs) have emerged as basic structural and functional units of genome organization, and have been determined by many computational methods from Hi-C contact maps. However, the TADs obtained by different methods vary greatly, which makes the accurate determination of TADs a challenging issue and hinders subsequent biological analyses about their organization and functions. Obvious inconsistencies among the TADs identified by different methods indeed make the statistical and biological properties of TADs overly depend on the method we chose rather than on the data. To this end, we employ the consensus structural information captured by these methods to define the TAD separation landscape for decoding consensus domain organization of the 3D genome. We demonstrate that the TAD separation landscape could be used to compare domain boundaries across multiple cell types for discovering conserved and divergent topological structures, decipher three types of boundary regions with diverse biological features, and identify Cons ensus T opological A ssociating D omains (ConsTADs). We illustrate that these analyses could deepen our understanding of the relationships between the topological domains and chromatin states, gene expression, and DNA replication timing. In short, we provide an alternative solution to deal with the serious inconsistencies of TADs obtained via different methods by defining the TAD separation landscape and ConsTAD.