Loop extrusion, chromatin crosslinking, and the geometry, topology and mechanics of chromosomes and nuclei

The chromosomes of cells are based on tremendously long DNA molecules that must be replicated and then physically separated to allow successful cell division. Our group uses biophysical and mathematical approaches to study chromosome structure and dynamics. A key emerging feature of chromosome organization is the role of active chromatin loop formation, or "loop extrusion" as a mechanism underlying chromosome compaction, individualization, and segregation, as well as maintenance of regulatory chromatin loops. I will discuss experiments on SMC complexes (condensin, cohesin and SMC5/6 in eukaryotes), currently thought to be the loop-extruding elements, and how those experiments inform us on the mechanisms of these novel chromatin-organizing motors. For whole chromosomes, compaction via formation of tightly packed loops is combined with chromatin-chromatin interactions to achieve individualization of chromosomes and separation of adjacent chromatids during cell division. I will also discuss our group's studies of the role of chromosomal epigenetic marks in control of the structure and integrity of the cell nucleus, with a focus on the role of the balance between heterochromatin and euchromatin in controlling nuclear mechanics. I will discuss experiments on human cell nuclei that have established that the epigenetic "reader" HP1 plays a key role in controlling nuclear mechanics, presumably via "crosslinking" H3K9me2,3 marks on nucleosomes and thereby stabilizing mechanically robust heterochromatin domains. Our current experiments are probing the mechanics of the centromere, a highly robust complex of proteins and DNA, which appears to be uniquely resistant to disruption of its nucleic acid content.