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. 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 and observed de novo chromatin opening specifically in the replicated fraction. These opening events created an accessibility landscape similar to that seen in later time points, and binding of lineage-specific transcription factors was enriched in these regions. Opening of these regions was impaired when replication was inhibited during early reprogramming. 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.