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

The chromosomes of eukaryotic cells are based on tremendously long DNA molecules that must be replicated and then physically separated to allow successful cell division. I will discuss what we have learned about chromosome structure from our group's biophysical experiments and mathematical modeling of chromosome structure. A key emerging feature of chromosome organization is the role of active chromatin loop formation, or "loop extrusion" as a mechanism leading to chromosome compaction, individualization, and segregation. I will discuss our work on physics-based modeling of the SMC complexes thought to be the loop-extruding elements. I will also discuss our group's studies of the role of chromatin and epigentic mark-crosslinking "readers" in control of global structure and integrity of the interphase nucleus. We have found that disruption of elements key to heterochromatin - specifically histone H3K9 methylation or levels of the heterchromatin protein HP1α - leads to weakening, shape destabilization, and rupture of nuclei, indicating a structural role for heterochromatin in maintaining normal nuclear organization.