Activity-driven chromatin organization during interphase: compaction, segregation, and overlap suppression

In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase to form dynamic loops through a process known as active loop extrusion. We develop a theory demonstrating that active loop extrusion causes the apparent fractal dimension of chromatin to cross over between two and four at contour lengths on the order of 30 kilo-base pairs (kbp). The anomalously high fractal dimension of D=4 is due to the inability of extruded chromatin loops to fully relax during active extrusion. Compaction on longer contour length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Furthermore, cohesin motion couples to chromatin conformation formed by other extruding cohesins. Extrusion-induced compaction suppresses overlaps such that 400 kbp TADs are mostly segregated and the genomic length of entangled chromatin sections increases to be on the order of Mega-base pairs. We validate our results with hybrid molecular dynamics – Monte Carlo simulations and show that our theory is consistent with experimental data. This work provides a theoretical basis for the compact organization of interphase chromatin explaining the physical reason for segregation of TADs and suppression of chromatin entanglements which contribute to efficient gene regulation.