Reversing aging-like 3D genome disorganization in a Drosophila interphase model
Year: 2026
Type: preprint
Abstract: Recent experimental evidence suggests that aging may arise from the progressive deterioration of the epigenetic landscape, while reversing the trend can result in cell and tissue rejuvenation. A mechanistic understanding of how restoration of a key component of this landscape – the 3D structure of the genome – can be accomplished is lacking. Here we investigate the lamina-dependent disruption and recovery of the 3D architecture of the Drosophila melanogaster genome at topologically associating domains (TADs) resolution (∼ 100 kb), using a model of the entire nucleus; weakening of chromatin-lamina interactions mimics a loss of chromatin organization associated with aging. We characterize this loss using the Shannon entropy of the appropriately normalized Hi-C contact and by deterioration of the chromosome territories. Our main finding is that increase in Hi-C map disorder and deterioration of chromosome territories induced by lamina depletion are largely reversible when the wild-type (WT)-like Lamina-associated domain (LAD)– nuclear-envelope interactions are restored; the original and recovered conformational states of chromatin are essentially indistinguishable by the bulk Hi-C contact matrix, and the recovered WT state of chromatin remains stable. The recovery is robust: we find that the WT-like 3D architecture can also be recovered from a more severely perturbed lamina-depleted and compartment-disrupted state, in which all attractive interactions have been switched off. The direct experimentally testable prediction is that the restoration of functional LAD– lamina interactions will promote recovery of the WT-like 3D chromatin architecture after lamina-dependent architectural disruption. We further hypothesize that lamin restoration may increase lifespan of the fruit fly and improve other aging-associated phenotypes through the recovery of young-like LAD– lamina attachments.
Institution: Virginia Tech
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7170053439