Reversing aging-like 3D genome disorganization in a Drosophila interphase model

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.