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

Mol Cell. 2018 Jun 21;70(6):1121-1133.e9. doi: 10.1016/j.molcel.2018.05.015. Epub 2018 Jun 14.


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.

Keywords: COMPASS; H3K4me; H3K56ac; PAF1C; expression homeostasis; histone modifications; replication checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Cycle Checkpoints / genetics
  • DNA Replication / genetics
  • DNA Replication / physiology*
  • Epigenesis, Genetic / physiology
  • Epigenomics / methods
  • Gene Expression Regulation, Fungal / genetics
  • Histone Acetyltransferases / metabolism
  • Histone Methyltransferases / metabolism
  • Histones / metabolism*
  • Histones / physiology
  • Homeostasis / genetics
  • Lysine / metabolism
  • Nuclear Proteins / metabolism
  • Protein Processing, Post-Translational / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / metabolism


  • Histones
  • Nuclear Proteins
  • PAF1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • histone H3 trimethyl Lys4
  • Histone Methyltransferases
  • Histone Acetyltransferases
  • Lysine