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.