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

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 lamina-dependent disruption and recovery of the 3D architecture of the Drosophila melanogaster genome at TAD resolution ([~] 100 kb), using a model of the entire nucleus; weakening of chromatin-lamina interactions mimics an aging-associated loss of chromatin organization. We characterize this loss using the Shannon entropy of appropriately normalized Hi-C contact matrices. Our main finding is that lamina-depletion-induced increases in Hi-C map disorder, deterioration of chromosome territories, and cell-to-cell conformational heterogeneity are largely reversible when WT-like LAD-nuclear-envelope interactions are restored. The original and recovered conformational states of chromatin are nearly indistinguishable by bulk Hi-C contact matrix; the corresponding Pearson correlation coefficient is 0.999902. The direct experimentally testable prediction is that restoration of functional LAD-lamina interactions will promote recovery of young/WT-like 3D chromatin architecture after lamina-dependent architectural disruption.