Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging.

Nuclear deformation, a hallmark frequently observed in senescent cells, is presumed to be associated with the erosion of chromatin organization at the nuclear periphery. However, how such gradual changes in higher-order genome organization impinge on local epigenetic modifications to drive cellular mechanisms of aging has remained enigmatic. Here, through large-scale epigenomic analyses of isogenic young, senescent, and progeroid human mesenchymal progenitor cells (hMPCs), we delineate a hierarchy of integrated structural state changes that manifest as heterochromatin loss in repressive compartments, euchromatin weakening in active compartments, switching in interfacing topological compartments, and increasing epigenetic entropy. We found that the epigenetic de-repression unlocks the expression of pregnancy-specific beta-1 glycoprotein (PSG) genes that exacerbate hMPC aging and serve as potential aging biomarkers. Our analyses provide a rich resource for uncovering the principles of epigenomic landscape organization and its changes in cellular aging and for identifying aging drivers and intervention targets with a genome-topology-based mechanism.