Cell fate reprogramming through engineering of native transcription factors

Abstract

Cellular reprogramming using cocktails of transcription factors (TFs) affirms the epigenetic and developmental plasticity of mammalian cells. It demonstrates the ability of TFs to ‘read’ genetic information and to rewire regulatory networks in different cellular contexts. Silenced chromatin is not an impediment to the genome engagement by ectopically expressed TFs. Reprogramming TFs have been identified in diverse structural families that lack shared domains or sequence motifs. Interestingly, the reprogramming activity of non-redundant paralogous TFs can be switched with a few point mutations. These findings revealed that the sequence–function relationships influencing reprogramming are tied to subtle features directing genome wide binding. Therefore, endogenous reprogramming TFs are amenable to directed biomolecular engineering that opens up new avenues to optimize cell fate conversions.