RBBP5 is an epigenetic regulator of mammalian hepatic 12h oscillator

While the upstream proteostatic stress-sensing and protein-folding mechanisms in the ER and cytosol are well studied, the transcriptional regulation of proteostasis remains incompletely understood, particularly concerning the temporal epigenome dynamics, chromatin landscapes, and co-regulatory networks underlying dynamic proteostasis control.

Traditionally, proteostatic stress responses were viewed as acute reactions to noxious stimuli, but recent evidence shows that many proteostasis genes exhibit ~12-hour ultradian rhythms under physiological conditions, driven by a XBP1s-dependent oscillator independent of the canonical circadian clock and cell cycle. By mapping the chromatin landscape of the murine 12-hour oscillator, we identified RBBP5—an essential subunit of the COMPASS complex responsible for H3K4 trimethylation—as a pivotal epigenetic regulator of proteostasis dynamics.