SUMMARY
Topologically associating domains (TADs) are critical for gene regulation. Current views attribute TAD formation to cohesin-mediated extrusion and ignore the role of physical properties of in vivo chromatin. Here, we demonstrate that the two universal properties: chromatin fluidlike behavior and heterogeneity in DNA-packing density along chromatin, can drive TAD formation. We use DNA-accessibility data to parameterize DNA-packing density along chromatin and simulate stochastic folding of the heterogeneous chromatin in nucleus to yield a conformation ensemble. Such an ensemble can be cross-validated by Hi-C and FISH data. Furthermore, the stochastic folding model allows de novo prediction of the establishment and disappearance of key TADs during early T cell differentiation. Together, our work demonstrates that the intrinsic stochastic folding of fluidlike chromatin leads to the prevalence of TAD-like domains in single cells and their cell-to-cell variation, while the heterogeneity in DNA-packing density along chromatin mediates the emergence of TADs at ensemble-averaged level.
In brief A study based on polymer simulation reveals that the two universal physical properties of in vivo chromatin fiber: chromatin fluidlike behavior and heterogeneity in DNA-packing density along chromatin play a vital role in TAD formation.
Highlights
Intrinsic stochastic folding of fluidlike chromatin in nuclear space underlies the prevalence of TAD-like domains in single cells and their cell-to-cell variation
Heterogeneity in DNA-packing density along chromatin causes the emergence of TADs at ensemble-averaged level
The disappearance and establishment of key TADs during early T cell differentiation can occur through a stochastic folding process alone, without the need of any cohesin-mediated chromatin extrusion
The stochastic folding model applies to diverse cell types and is thus able to de novo predict the dynamics of genome organization over time
Competing Interest Statement
The authors have declared no competing interest.
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