Single-molecule mechanics of eukaryotic and bacterial SMC complexes

Gene expression is tuned by enhancer-promoter interactions (EPIs) within a three-dimensional genome that is constantly in motion. Neurons take this problem to its limit: they are post-mitotic and long-lived, and they depend on regulatory elements acting across megabase distances. Consequently, mutations in chromatin regulators and alterations in genome topology cause neurodevelopmental disorders, and in other contexts as cancer. However, the principles governing how EPIs are established, maintained, and lost during differentiation remain poorly understood, largely because most measurements are static snapshots of fixed cell populations.

This seminar follows a single question from disease genetics to biophysics to engineering: which chromatin-regulator genes are responsible for neurodevelopmental disorders and what the downstream phenotypic consequences of their mutations are; how those regulators physically act in single living cells, where chromatin contacts prove to be dynamic, rare, and short-lived rather than stable structures; and whether that mechanistic picture can be inverted into design, engineering EPIs and 3D genome architecture in neurons.

Together, these lines of inquiry chart a multidisciplinary path from disease-gene discovery, through single-molecule biophysics, to chromatin engineering in the cells where it matters most.