Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

Abstract

Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are highly resistant to reprogramming. There must be barriers that 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 a variety of oncogenic transgenes, and discovered transformed cell lines that remain 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 very early, whilst other lines seemed to progress through a normal-looking reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperactive epigenetic state in some of the transformed cells. This study reveals that the barriers underlying resistance to reprogramming vary between the different transformation methods. Key findingsO_LISomatic cell reprogramming of transformed cells is context-specific C_LIO_LIInhibition of MEK converts some cell lines to reprogramming-capable C_LIO_LITransformed cell lines are characterized by a hyperactive chromatin state C_LIO_LIMEK inhibition indirectly affects chromatin to enable reprogramming C_LI