Nuclear expansion drives chromatin structure remodeling in aging neurons

Aging, particularly in the brain, involves impairments in multiple cellular and molecular functions, many of which are regulated at the nucleus. Chromatin structure plays a critical role in the regulation of gene expression and the maintenance of genomic stability. During differentiation, chromosomes acquire their unique topology depending on the cell type that should be kept for a lifetime, but this may deteriorate as we age. However, the effects of aging on the chromatin 3D structure of neurons remain largely unknown and much has been inferred from senescent cells. By combining chromosome conformation capture and microscopy techniques, we investigated cortical neurons of young and aged mice and discovered neuronal nuclear expansion during neuronal aging, leading to increased distances between chromosomes. This expansion alters the topology of compartments, topologically associating domains (TADs) and chromatin loops. While larger TADs tend to dissociate, smaller TADs and loops exhibit strengthened interactions to maintain the cohesiveness of chromatin in aged neurons. These topological changes impact the borders of TADs, resulting in their overall weakening. Interestingly, we attribute these alterations to changes in the physical forces of an expanding nucleus, filling a growing nuclear area, affecting downstream gene expression and chromatin topology, further contributing to the functional declines observed during aging. We performed Hi-C in neurons isolated using FACS from the cortex tissue of the aging, adult, and control mice.