Chromosome Organization by Loop Extrusion and Phase Separation

Inferring principles and mechanisms of 3D organization of chromosomes from Hi-C and imaging data is a challenging biophysical problem. Our works suggest that chromosomes are organized by a process of loop extrusion. We proposed that loop extrusion is a universal mechanism responsible for formation of domains in interphase [1,2], and chromosome compaction and segregation in metaphase [3]. I will review recent experimental studies [3-5] that provide strong support to loop extrusion as a universal mechanism of chromosome folding. These experiments have also showed that spatial segregation of euchromatin and heterochromatin is achieved by a different mechanism. To elucidate mechanisms of this spatial segregation, we examined Hi-C and microscopy for cells with inverted nuclei and conventional nuclear architecture [6]. Polymer model base on these data show that attraction between heterochromatic regions drive the phase separation, while interactions with the lamina central for spatial positioning of phases in the nucleus. Taken together our results demonstrate two major processes shape chromosome organization through the cell cycle: heterochromatin-driven phase segregation and SMC-driven loop extrusion. 1. Fudenberg G, Imakaev M, et al. Formation of Chromosomal Domains by Loop Extrusion. Cell Rep (2016) 2. Goloborodko A, Imakaev MV, Marko JF, Mirny L. Compaction and segregation of sister chromatids via active loop extrusion. Elife. May 18;5 (2016) 3. Nora EP, et al. Targeted degradation of CTCF decouples local insulation of chromosome domains from higher-order genomic compartmentalization Cell (2017) 4. Schwarzer W, Abdennur N, et al., Two independent modes of chromosome organization are revealed by cohesin removal Nature (2017) 5. Gibcus J, Samejima K, Goloborodko A, et al., Mitotic chromosomes fold by condensin-dependent helical winding of chromatin loop arrays Science (2018) 6. Falk M, Feodorova Y Naumova N, et al., Heterochromatin drives organization of conventional and inverted nuclei https://www.biorxiv.org/content/early/2018/01/09/24403