Spontaneous whole genome duplication renders mouse embryonic fibroblasts resistant to reprogramming

Whole-genome duplication (WGD) is thought to be quite rare, but has important implications ranging from emergences of new species to tumorigenesis. The burden of doubled genome for a cell must be traumatic and remains poorly understood. Here we report a spontaneous and robust WGD system amicable to detailed molecular analysis. We first show that mouse embryonic fibroblasts (MEFs) undergo spontaneous WGD in vitro. The resulting binucleated cells or BNCs become resistant to iPSC reprogramming. We further show that pretreating MEFs with p38 inhibitor SB203580 suppresses WGD and enhances reprogramming. Mechanistically, we demonstrate the WGD activates p53 in BNCs to act as the primary barrier to reprogramming, as its depletion rescues iPSC formation in tetraploid cells. These findings provide a convenient WGD experimental system and our preliminary analysis reveals p38 coordinates WGD progression and p53 regulates subsequent cell fate determination in genome-doubled cells.