Engineering Synthetic Cell State Transitions by Harnessing Epigenetic Memory

During development, cell-cell communication induces state transitions that are maintained by epigenetic regulation. Here, we harness endogenous epigenetic silencing machinery to engineer synthetic circuits that induce stable gene expression changes. Using synthetic Notch receptors that control the chromatin regulators KRAB and Dnmt3L, we developed input-sensing switches that induce self-sustained silencing of target loci. We used these modules to construct circuits in which combinatorial inputs direct a choice among multiple alternative states. These epigenetic switches can also be inverted to yield sustained activation of target genes. We demonstrate that these epigenetic switches can be used to drive morphological changes triggered by transient cell-cell interactions, but that remain stable over many cell divisions, as is observed in development. Additionally, these circuits can be used to drive the reprogramming of fibroblasts to a neuron-like state. These synthetic epigenetic circuits represent an important step towards engineering cell populations capable of coordinated multi-cell state decisions.