Polymer models of mitotic and interphase chromosomes

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PROJECT SUMMARY The spatial organization of chromosomes has long been connected to their polymeric nature and is believed to be important for their biological functions, including the control of interactions between genomic elements, the maintenance of genetic information, and the compaction and safe transfer of chromosomes to cellular progeny. Chromosome conformation capture techniques, particularly Hi-C, and microscopy have provided a comprehensive picture of spatial chromosome organization and revealed new features and elements of chromosome folding. Polymer models and new perturbation data generated in the last two years have led to the identification of novel molecular mechanisms behind large-scale genome organization. Two major mechanisms discovered in the course of this project have moved the field forward. First, is the active (ATP-dependent) process of loop extrusion by Structural Maintenance of Chromosomes (SMC) complexes. This universal mechanism underlies formation of domains in the interphase, and chromosome compaction and segregation in mitosis. Second, is the affinity-mediated interactions between heterochromatic regions that drive spatial compartmentalization of the genome at the scale of the whole nucleus. Proposed project aimed at examining mechanisms of loop extrusion, understanding how gene expression and affect extrusion and hence refold chromosomes, and, finally, developing methods to detect loop extrusion in vivo by combination of polymer simulations and live cell imaging. Together, these aims could show whether and how loop extrusion operates in vivo, opening avenues to understand it functional roles and molecular mechanisms.