RT Journal Article
SR Electronic
T1 Single-cell absolute contact probability detection reveals that chromosomes are organized by modulated stochasticity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 159814
DO 10.1101/159814
A1 Diego I. Cattoni
A1 Andrés M. Cardozo Gizzi
A1 Mariya Georgieva
A1 Marco Di Stefano
A1 Alessandro Valeri
A1 Delphine Chamousset
A1 Christophe Houbron
A1 Stephanie Déjardin
A1 Jean-Bernard Fiche
A1 Marc A. Marti-Renom
A1 Frédéric Bantignies
A1 Giacomo Cavalli
A1 Marcelo Nollmann
YR 2017
UL http://biorxiv.org/content/early/2017/07/05/159814.abstract
AB The multi-scale organization of eukaryotic genomes defines and regulates cellular identity and tissue-specific functions1–3. At the kilo-megabase scales, genomes are partitioned into self-interacting modules or topologically associated domains (TADs) 4–6. TADs formation seems to require specific looping interactions between TAD borders 7,8, while association of TADs can lead to the formation of active/repressed compartments 9. These structural levels are often seen as highly stable over time, however, recent studies have reported different degrees of heterogeneity 10,11. Access to single-cell absolute probability contact measurements between loci and efficient detection of low-frequency, long-range interactions is thus essential to unveil the stochastic behaviour of chromatin at different scales. Here, we combined super-resolution microscopy with state-of-the-art DNA labeling methods to reveal the variability in the multiscale organization of chromosomes in different cell-types and developmental stages in Drosophila. Remarkably, we found that stochasticity is present at all levels of chromosome architecture, but is locally modulated by sequence and epigenetic state. Contacts between consecutive TAD borders were infrequent, independently of TAD size, epigenetic state, or cell type. Moreover, long-range contact probabilities between non-consecutive borders, the overall folding of chromosomes, and the clustering of epigenetic domains into active/repressed compartments displayed different degrees of stochasticity that globally depended on cell-type. Overall, our results show that stochasticity can be specifically modulated to give rise to different levels of genome organization. We anticipate that our results will guide new statistical models of genome architecture and will be a starting point for more sophisticated studies to understand how a highly variable, multi-scale organization can ensure the maintenance of stable transcriptional programs through cell division and during development.