At the level of higher-order chromosome folding, the physical nature of structural domains such LADs and CIDs/TADs will be illuminated by single-cell techniques. A central question is whether these domains are constant in all cells or appear, possibly transiently, in smaller fraction of cells. For example, pioneering studies of LADs in single cells (Kind et al. 2013) showed that only ∼30% of LADs identified from ensemble measurements are actually attached to the nuclear periphery in any individual cell. A similar question arises from 3C-based assays, where any genomic locus that exhibits interactions with two or more other regions in ensemble measurements could, in principle, result from locus X interacting in a cluster (e.g., a “transcription factory”) with both locus Y and Z in the same cell, or a population of cells with distinct subsets of cells with either X-Y interactions or X-Z interactions. More concretely, the abundant interactions occurring throughout a megabase chromosomal domain such as a TAD/CID can be conceptualized as a globular domain in which all interacting pairs of chromosome fragments are in close proximity in a given
