2025 Theses Doctoral

Nucleocytoskeletal connections in gene expression and chromatin accessibility

Wilson, Paige

The linker of nucleoskeleton and cytoskeleton (LINC) complex transmits mechanical forces from the cytoskeleton to the nuclear interior in a wide array of cellular processes. There is growing evidence that the LINC complex is an important regulator of gene expression and chromatin organization. However, the relative influence of its nucleocytoskeletal linkages in regulating transcriptional programs and chromatin organization is unresolved.

This dissertation focuses on the giant KASH protein nesprin-2G, which interacts with both actin and microtubules, to dissect how its cytoskeletal connections shape transcriptional programs and chromatin accessibility. Using targeted depletion of endogenous nesprin-2G in fibroblasts, combined with genome-wide transcriptomic and chromatin-accessibility profiling, I demonstrate that nesprin-2G is required to maintain basal transcriptional activity and an open chromatin landscape. By re-expressing nesprin-2G-cytoskeletal interacting domains individually and together, I identified the first function of nesprin-2G that requires both its actin- and microtubule-interactions. This thesis advances a model in which domain-specific tension-sensing within a single KASH protein couples cellular mechanics to genome organization and chromatin organization.