The chromosome folding problem and how cells solve it

Abstract

Every cell must solve the problem of how to fold its genome. We describe how the folded state of chromosomes is the result of the combined activity of multiple conserved mechanisms. Homotypic affinity-driven interactions lead to spatial partitioning of active and inactive loci. Molecular motors fold chromosomes through loop extrusion. Topological features such as supercoiling and entanglements contribute to chromosome folding and its dynamics, and tethering loci to sub-nuclear structures adds additional constraints. Dramatically diverse chromosome conformations observed throughout the cell cycle and across the tree of life can be explained through differential regulation and implementation of these basic mechanisms. We propose that the first functions of chromosome folding are to mediate genome replication, compaction, and segregation and that mechanisms of folding have subsequently been co-opted for other roles, including long-range gene regulation, in different conditions, cell types, and species.