Luca Giorgetti, PhD
Group Leader
Friedrich Miescher Institute for Biomedical Research
A quantitative analysis of the hierarchical folding of mammalian chromosomes
Understanding how regulatory sequences such as enhancers and promoters interact in the context of chromosomal architecture is a central challenge in biology. Chromosome conformation capture methods revealed that mammalian chromosomes possess a rich hierarchy of structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs), further partitioned into sub-TAD structures such as contact domains and CTCF/cohesin-associated loops. TADs appear to act as regulatory microenvironments by constraining and segregating regulatory interactions across discrete chromosomal regions. However, it remains unclear whether other (or all) folding layers share similar properties, or rather TADs constitute a privileged folding scale with maximal impact on the organization of regulatory interactions. To address this question, we have developed a novel algorithm named CaTCH that identifies hierarchical trees of chromosomal domains in Hi-C maps, stratified through their reciprocal physical insulation, which is a single and biologically relevant parameter. By applying CaTCH to several Hi-C datasets, we demonstrate that although no structurally privileged folding level exists, TADs emerge as a functionally privileged scale defined by maximal boundary enrichment in CTCF and maximal cell-type conservation. We also show that the likelihood that genes in a domain are co-regulated during differentiation is also maximized at the scale of TADs. Finally, we observe that regulatory sequences occur at genomic locations corresponding to optimized mutual interactions at the same scale. Our analysis suggests that the architectural functionality of TADs arises from the interplay between their ability to partition interactions and the specific genomic positions of regulatory sequences.
