A general strategy for cellular reprogramming: the importance of transcription factor cross-repression

Transcription factor cross-repression is an important concept in cellular differentiation. A bistable toggle switch constitutes a molecular mechanism that determines cellular commitment and provides stability to transcriptional programs of binary cell fate choices. Experiments support that perturbations of these toggle switches can interconvert these binary cell fate choices, suggesting potential reprogramming strategies. However, more complex types of cellular transitions could involve perturbations of combinations of different types of multistable motifs. Here, we introduce a method that generalizes the concept of transcription factor cross-repression to systematically predict sets of genes, whose perturbations induce cellular transitions between any given pair of cell types. Furthermore, to our knowledge, this is the first method that systematically makes these predictions without prior knowledge of potential candidate genes and pathways involved, providing guidance on systems where little is known. Given the increasing interest of cellular reprogramming in medicine and basic research, our method represents a useful computational methodology to assist researchers in the field in designing experimental strategies.