Order and stochasticity in the folding of individual Drosophila genomes

Overview & Synopsis

Mammalian and Drosophila genomes are partitioned into Topologically Associating Domains (TADs) [ref]. Although this partitioning was reported to be functionally relevant [ref], it is unclear whether TADs represent true physical units in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, applying an improved single-nucleus Hi-C technique (snHi-C), we constructed Hi-C maps in individual Drosophila genomes with a 10 kb resolution. These maps demonstrate chromatin compartmentalization at the megabasescale and partitioning of the genome into non-hierarchical TADs at a scale of 100 kb, which closely resembles the TAD profile in the population Hi-C data. Over 45% of TAD boundaries possess a high level of active epigenetic marks and are conserved between individual nuclei. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is best approximated by crumpled globule build of Gaussian blobs at longer distances. We observed prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, arguing for an important contribution of stochastic processes to the formation of the Drosophila 3D genome.