Post-replicative chromatin accessibility predicts cell fate change.

It has long been hypothesized that DNA replication is important in reconfiguring the chromatin landscape during cell identity changes in development, disease, and reprogramming contexts. There is now a large body of work showing that DNA replication indeed alters chromatin structure and composition, but a function for these changes has remained elusive. Using replication-coupled ATAC-seq in differentiating embryonic stem cells and reprogramming mouse embryonic fibroblasts, we profiled replicated and unreplicated chromatin within the same cells and observed de novo chromatin opening specifically in the replicated fraction. These opening events created an accessibility landscape similar to that seen in the unreplicated fraction from later timepoints, especially in reprogramming. By parsing reprogramming fibroblasts based on proliferative history, we confirmed that reprogramming potential can be predicted by proliferation rate. This work bridges the gap between replication-induced structural chromatin changes and functional consequences by demonstrating that replication facilitates a “window of opportunity” that advances the chromatin landscape during cell identity change. Overall design: repli-ATAC-seq time series in differentiating mouse embryonic stem cells and reprogramming mouse fibroblasts, and ATAC-seq in reprogramming mouse fibroblasts sorted based on CellViolet proliferation staining.