Expression Homeostasis during DNA Replication

Genome replication introduces a step-wise increase in the DNA template available for transcription. Genes replicated early in S-phase experience this increase before late-replicating genes, raising the question of how expression levels are affected by DNA replication. We show that in budding yeast, mRNA synthesis rate is buffered against changes in gene dosage during S-phase. This expression homeostasis depends on acetylation of H3 on its internal K56 site by Rtt109/Asf1. Deleting these factors, mutating H3K56 or upregulating its deacetylation, increases gene expression in S-phase in proportion to gene replication timing. Therefore, H3K56 acetylation on newly deposited histones reduces transcription efficiency from replicated DNA, complementing its role in guarding genome stability. Our study provides the first molecular insight into the mechanism maintaining expression homeostasis during DNA replication.