Restricting epigenetic activity promotes the reprogramming of transformed cells to pluripotency in a line-specific manner.

Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are resistant to reprogramming. Epigenetic barriers must block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using oncogenic transgenes and discovered transformed cell lines compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed at an early stage, whilst other lines seemed to progress through a conventional reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperacetylated active epigenetic state. This study reveals that diverse epigenetic barriers underly resistance to reprogramming of transformed cells.