Epigenetic Control of Expression Homeostasis during Replication Is Stabilized by the Replication Checkpoint

DNA replication introduces a dosage imbalance between early and late replicating genes. In budding yeast, buffering gene expression against this imbalance depends on marking replicated DNA by H3K56 acetylation (H3K56ac). Whether additional processes are required for suppressing transcription from H3K56ac-labeled DNA remains unknown. Here, using a database-guided candidate screen, we find that COMPASS, the H3K4 methyltransferase, and its upstream effector, PAF1C, act downstream of H3K56ac to buffer expression. Replicated genes show reduced abundance of the transcription activating mark H3K4me3 and accumulate the transcription inhibitory mark H3K4me2 near transcription start sites. Notably, in hydroxyurea-exposed cells, the S phase checkpoint stabilizes H3K56ac and becomes essential for buffering. We suggest that H3K56ac suppresses transcription of replicated genes by interfering with post-replication recovery of epigenetic marks and assign a new function for the S phase checkpoint in stabilizing this mechanism during persistent dosage imbalance.