Recipes and mechanisms of cellular reprogramming: a case study on budding yeast Saccharomyces cerevisiae

We present here a systems biology approach that allows systematic search for effective reprogramming recipes and monitoring the reprogramming progress to uncover the underlying mechanisms. Using budding yeast as a model system, we have curated a genetic network regulating cell cycle and sporulation. Phenotypic consequences of perturbations can be predicted from the network without any prior knowledge, which makes it possible to computationally reprogram cell fate. As the heterogeneity of natural cells is important in many biological processes, we find that the extent of this heterogeneity restored by the reprogrammed cells varies significantly upon reprogramming recipes. The heterogeneity difference between the reprogrammed and natural cells may have functional consequences.Our study reveals that cellular reprogramming can be achieved by many different perturbations and the reprogrammability of a cell depends on the heterogeneity of the original cell state. We provide a general framework that can help discover new recipes for cellular reprogramming in human.In response to environmental or developmental signals, eukaryote cells normally transit to a specific state defined by the realization of its genetic network that specifies the gene expression and protein abundance levels. In the landscape of the cell state space, there exist attractors corresponding to different cell fates [1-4] and barriers between these attractors constrain cells to one attractor (one cell fate). Perturbations such as overexpression of a set of genes may push cells overcome the barriers and thus move from one attractor to another in the cell state space. An example is the generation of induced pluripotent stem cells (iPSCs) from differentiated somatic cells by overexpression of several genes [5-8]. A challenging problem is how to efficiently find effective, ideally the optimal, perturbations to reprogram a cell's fate. In addition, there are other unanswered questions such as how exactly cellu