Abstract
BackgroundGenome organization into subchromosomal topologically associating domains (TADs) is linked to cell-type-specific gene expression programs. However, dynamic properties of such domains remain elusive, and it is unclear how domain plasticity modulates genomic accessibility for soluble factors.ResultsHere, we combine and compare a high-resolution topology analysis of interacting chromatin loci with fluorescence correlation spectroscopy measurements of domain dynamics in single living cells. We identify topologically and dynamically independent chromatin domains of ~1 Mb in size that are best described by a loop-cluster polymer model. Hydrodynamic relaxation times and gyration radii of domains are larger for open (161 ± 15 ms, 297 ± 9 nm) than for dense chromatin (88 ± 7 ms, 243 ± 6 nm) and increase globally upon chromatin hyperacetylation or ATP depletion.ConclusionsBased on the domain structure and dynamics measurements, we propose a loop-cluster model for chromatin domains. It suggests that the regulation of chromatin accessibility for soluble factors displays a significantly stronger dependence on factor concentration than search processes within a static network.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0093-1) contains supplementary material, which is available to authorized users.
Highlights
Genome organization into subchromosomal topologically associating domains (TADs) is linked to cell-type-specific gene expression programs
The results presented here provide a missing link between chromatin organization maps that reveal the subchromosomal domain structure at steady state from 3C-type analyses and the dynamic properties of these compartments measured here by fluorescence correlation spectroscopy (FCS)
We conclude that the highly dynamic nature of domains observed in our study provides an additional constraint on three-dimensional modeling of chromatin structure for 3C-type data: A high contact probability can only result from sufficiently stable physical contact between two loci, otherwise the pronounced fluctuations would effectively segregate them
Summary
Genome organization into subchromosomal topologically associating domains (TADs) is linked to cell-type-specific gene expression programs. The resulting translocation data can be quantified as mean-squared displacement (MSD) versus time curves to extract apparent velocities or diffusion coefficients These studies revealed spatially confined movements of tagged chromatin loci as intuitively evident for a segment of a polymer without center-of-mass translocation [38,39,40]. Methods like fluorescence recovery after photobleaching (FRAP), continuous photobleaching (CP) and fluorescence correlation spectroscopy (FCS) provide information on the binding of proteins to chromatin and on their mobility within the chromosomal environment on the microsecond to minute time scale [42, 43] With these methods no information on the dynamics of nucleosome chains and higher-order domains has yet been obtained. Our current knowledge is lacking both experimental information and theoretical treatment of the conformational dynamics of chromatin in vivo that is important for the understanding of the differential readout of DNA sequence information or interactions between different genomic loci
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