DNA replication timing alterations identify common markers between distinct progeroid diseases

Significance We show that the temporal order of replication (replication timing, RT), normally an extremely stable cell type-specific chromosomal property, is altered in cells from two different premature aging (progeroid) diseases. By converting patient cells to stem cells and redifferentiating them as a model of disease progression, we identified the TP63 gene as one of the earliest RT alterations and altered RT was associated with abnormal TP63 gene expression. TP63 mutations have been linked to other diseases that share clinical features of progeroid syndromes. These findings introduce an approach for disease marker discovery, identify molecular abnormalities distinguishing progeroid diseases from natural aging, and point to TP63 as a molecular link to the pathophysiological manifestations of progeroid diseases.