Cell https://doi.org/10.1016/j.cell.2018.11.002 (2018)
Chemical modifications on DNA and histones play important roles in a wide range of biological processes, and can also enable gene expression memory (epigenetics). It is challenging to study the underlying mechanism of epigenetic regulation because of the complexity of natural chromatin networks. To overcome this problem, Park et al. utilized a synthetic biology approach to construct de novo an epigenetic regulatory system based on N6-methyladenine (m6A) in mammalian cells. They attached a variant of an Escherichia coli DNA adenine methyltransferase (Dam) to an engineered zinc finger protein or dCas9 to generate a synthetic initiator module (synI). SynI can bind to specific sequences and introduce m6A at nearby GATC motifs in the promoter region of a reporter gene. When combined with engineered m6A reader modules, their systems can activate or repress the expression of the reporter. They also constructed a three-module circuit by introducing an additional read–write (RW) module, which can propagate m6A modifications along DNA and also maintain epigenetic memory during cell division. This synthetic approach provides a unique capability to study the quantitative design principles underlying chromatin spreading and heritable gene expression memory.