Stress triggers global histone synthesis in the liver.

Despite extensive drug development targeting DNA synthesis, there have been few efforts to inhibit histone synthesis, which occurs jointly with DNA synthesis in S-phase. A major roadblock is the lack of tools to quantitively measure histone synthesis due to the high abundance and stability of histone proteins. Here we present chemical labeling methodologies to produce the first in vivo measurements of histone synthesis rates. Under basal conditions, histone synthesis tracks closely with tissue proliferation. However, multiple systemic and liver-specific stresses induce a previously uncharacterized surge of hepatocyte nucleosome production that is uncoupled from DNA replication. Tracing of newly synthesized nucleosomes detected promoter deposition, which was required to buffer transcriptional output. These results may inform strategies to modulate histone production to influence stress responses or disease.