Histone dynamics at replication forks in embryonic stem cells

We employ inducible mutants to dissect the early and late consequences of impaired histone recycling. We find rapid accumulation of H3K27me3 in response to impaired histone recycling, preceding gene expression changes. Simultaneous disruption of both leading (POLE4) and lagging strand (MCM2-2A) recycling pathways impairs transmission of parental histones to new DNA, with release of parental histones to the soluble pool. This loss of histone inheritance alters gene expression in embryonic stem cells, challenges differentiation programs and compromises cell viability. Our findings demonstrate the importance of efficient transmission of histone-based information during DNA replication for maintaining chromatin landscapes, differentiation potential, and cellular viability.