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Topology of polymer chains under nanoscale confinement: insights into genome folding

This month, a paper was published in Nanoscale by scientists from Dr. Alireza Mashaghi group at the Systems Biomedicine and Pharmacology Division in collaboration with the group of Dr. Sander Tans from TU Delft/AMOLF. In this paper, the authors studied how nanoscale spatial confinement affects the fold topology of the genomic DNA. Genomic DNA is folded in the crowded and highly confined nuclear environment. Spatial confinement limits the conformational space accessible to genomic DNA but the implications for DNA fold topology are not yet known.

Novel topology approaches

Using novel topology approaches, the team led by Alireza Mashaghi discovered a simple rule that summarizes the impact of confinement on the fold topology of a linear polymer chain. Genomic DNA folds by forming intra-chain contacts whose pairwise arrangements can be categorized as parallel, series or cross. The team found that the fold topology is determined by the ratio between the size scale of the confinement (R) and the persistence length of the polymer chain (L). At low values of L/R, the entropy of the linear chain leads to the formation of independent contacts along the chain and accordingly, increases the fraction of series topology with respect to other topologies. However, at high L/R, the fractions of cross and parallel topologies are enhanced circuits with cross becoming predominant. At an intermediate confining regime, the authors identified a critical value of L/R, at which all topological states have equal probability. Moreover, the team had also an intriguing observation that the effect of confinement can be sensed at locations deep into the folded structure and far away from the confining structure. Radial distribution analysis of the topology revealed that the effects of confinement is more pronounced in the core region than on the confinement surface. Finally, genomic DNA is not only subjected to such “external” confinement but also experience internal restraints. Two months before, the team systematically studied the effects of internal confinements caused by molecular bridges on the DNA fold topologies and reported their results in PCCP journal. These two complementary studies together revealed engineering principles that govern genome folding; these principles can be exploited to develop therapeutic approaches to correct “misfolding” in disease conditions.  

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