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

Area of Science:

• Molecular Biology
• Epigenetics
• Gene Regulation

Background:

• DNA replication creates gene dosage imbalance between early and late replicating genes.
• H3K56 acetylation (H3K56ac) is crucial for buffering gene expression in budding yeast.
• The role of additional factors in suppressing transcription from H3K56ac-marked DNA is unclear.

Purpose of the Study:

• To identify additional processes that suppress transcription from H3K56ac-labeled DNA.
• To elucidate the mechanism by which H3K56ac buffers gene expression.
• To investigate the role of the S phase checkpoint in this buffering mechanism.

Main Methods:

• Database-guided candidate screen.
• Analysis of epigenetic marks (H3K4me3, H3K4me2) near transcription start sites.
• Hydroxyurea treatment to induce S phase checkpoint activation.

Main Results:

• COMPASS (H3K4 methyltransferase) and PAF1C act downstream of H3K56ac to buffer gene expression.
• Replicated genes exhibit decreased H3K4me3 and increased H3K4me2 near transcription start sites.
• The S phase checkpoint stabilizes H3K56ac and is essential for buffering in hydroxyurea-treated cells.

Conclusions:

• H3K56ac suppresses transcription of replicated genes by hindering epigenetic mark recovery.
• COMPASS and PAF1C are key players in the H3K56ac-mediated buffering pathway.
• The S phase checkpoint plays a novel role in stabilizing H3K56ac-dependent buffering during persistent DNA replication stress.