RBBP5 Emerges as a Master Epigenetic Switch Controlling the Cell’s 12-Hour Proteostasis Clock

Every cell in the body runs a continuous quality-control operation. Newly made proteins must fold into precise three-dimensional shapes, misfolded proteins must be refolded or destroyed, and damaged organelles must be recycled before they poison the cell. Biologists call this system proteostasis, and when it falters, the consequences are severe: the collapse of protein homeostasis is a hallmark of aging, neurodegenerative disease, and metabolic disorders. For decades, researchers have mapped the sensors and chaperones that respond to proteotoxic stress in the endoplasmic reticulum and the cytosol, but far less attention has been paid to how the genome itself is regulated to keep this machinery running. A new study published in PLOS Biology now identifies a surprising central player in that regulation: RBBP5, a core subunit of the histone methyltransferase complex known as COMPASS, which the authors show acts as a pivotal epigenetic regulator of proteostasis dynamics.

The discovery grew out of a shift in how scientists think about stress responses. Proteotoxic stress responses were traditionally viewed as acute, emergency reactions triggered by noxious stimuli such as heat, toxins, or chemical stressors. But recent evidence has revealed something more rhythmic and more fundamental. Many proteostasis genes do not simply wait for disaster to strike; instead, they oscillate on an approximately 12-hour ultradian cycle under ordinary physiological conditions. This 12-hour oscillator is driven by the transcription factor XBP1s in its spliced, active form, and remarkably, it operates independently of both the canonical circadian clock and the cell cycle. In other words, cells possess a second biological clock, running at twice the frequency of the daily rhythm, dedicated to the maintenance of the protein-folding machinery.

To understand how this oscillator is written into chromatin, the research team, led by Syeda Kubra, Michelle Sun, William Dion, Yu Bian, and senior author Bokai Zhu, mapped the chromatin landscape associated with the murine 12-hour oscillator. Their genome-wide survey pointed decisively toward one factor: RBBP5, an essential subunit of the COMPASS complex, the enzyme complex responsible for depositing trimethyl marks on lysine 4 of histone H3, a modification abbreviated H3K4me3. H3K4me3 is classically associated with active gene promoters, and the new findings place it at the heart of the temporal control of proteostasis gene expression. In contrast, the study found that histone acetyltransferases and the H3K9 acetylation mark were dispensable for the dynamic expression of proteostasis genes, sharpening the conclusion that methylation, rather than acetylation, is the decisive chromatin currency for this program.

The functional experiments were striking in their consistency. RBBP5 was not merely present at the right places at the right times; it was indispensable for the 12-hour oscillator itself. When the researchers depleted RBBP5, the rhythmic transcriptional pulses that normally drive proteostasis gene expression collapsed. Beyond the oscillator, RBBP5 proved essential for the transcriptional regulation of responses to diverse proteotoxic stresses, indicating that the same epigenetic machinery governs both the rhythmic, housekeeping side of proteostasis and the acute, emergency side of the program.

Mechanistically, the study offers a two-pronged model for how RBBP5 exerts its influence. First, RBBP5 acts as a coactivator of XBP1s, the spliced transcription factor that drives the 12-hour oscillator and the broader unfolded protein response. By partnering with XBP1s, RBBP5 helps translate the stress-sensing signal from the endoplasmic reticulum into a productive transcriptional output. Second, RBBP5 promotes the deposition of the H3K4me3 mark at the promoters of proteostasis genes, physically opening the chromatin at precisely the loci that encode chaperones, autophagy components, and other protein-quality-control factors. Together, these two functions make RBBP5 a bridge between the signaling layer of the stress response and the chromatin layer that must execute it.

The consequences of losing this bridge are immediate and measurable. The authors showed that loss of RBBP5 sensitizes cells to proteotoxic stress, in part because autophagy, the cellular recycling system that clears damaged proteins and organelles, becomes impaired. Autophagy is one of the major arms of the proteostasis network, and its dependence on RBBP5-dependent transcription explains why cells lacking this histone methyltransferase subunit cannot mount an effective defense when protein folding goes wrong. The finding suggests that chromatin competence, not just the presence of stress sensors, determines whether a cell survives proteomic insults.

To push the analysis beyond standard genomic assays, the team employed proximity labeling of H3K4me3, a technique that tags and identifies proteins found in the immediate vicinity of this histone mark in living cells. The resulting map uncovered a dynamic, chromatin-associated proteomic architecture that assembles at active proteostasis promoters during the stress response. Among the components identified were members of the COMPASS complex itself, the Integrator complex, a multi-subunit machinery best known for processing small nuclear RNAs and recently implicated in transcriptional pause release, and SWI/SNF chromatin remodelers, the ATP-dependent motors that physically reposition nucleotides to expose regulatory DNA.

This proteomic architecture is significant because it reframes the transcriptional response to proteotoxic stress as a coordinated, multi-complex event rather than the action of a single transcription factor. XBP1s may provide the sequence-specific targeting, but the actual execution depends on a choreographed assembly of methyltransferases, RNA-processing factors, and nucleosome remodelers converging on the same promoters. The proximity-labeling data suggest that this assembly is dynamic, forming and dissolving as the 12-hour oscillator cycles and as stress demands shift, providing a physical substrate for the temporal control of gene expression that the field has been seeking.

The broader implications reach into several of biomedicine’s most pressing territories. Because proteostasis decline is tightly linked to aging, the identification of an epigenetic regulator that sustains the proteostasis program offers a new target for interventions aimed at preserving cellular resilience. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where the accumulation of misfolded and aggregated proteins is a defining pathology, strategies that bolster RBBP5-dependent chromatin states could theoretically strengthen neurons’ capacity to cope with proteotoxic burdens. In metabolic disorders, where endoplasmic reticulum stress is a well-documented contributor to tissue dysfunction, the XBP1s-RBBP5 axis provides a mechanistic link between metabolic signaling and long-term chromatin competence.

The study also adds an important chapter to the biology of ultradian rhythms. The 12-hour oscillator, once regarded as a curiosity, is emerging as a physiologically meaningful clock with its own dedicated chromatin machinery. That RBBP5, a factor long appreciated simply as a core component of H3K4 methyltransferase complexes in development and gene regulation, turns out to be the linchpin of this clock illustrates how reexamining well-known molecular players in a rhythmic context can reveal entirely new functions. As the authors conclude, these findings establish RBBP5 as a central regulator of proteostasis dynamics, essential for maintaining cellular resilience, and they open a clear path for future work exploring how chromatin methylation could be therapeutically tuned to protect cells against the protein-folding failures that underlie aging and disease.

Subject of Research: Epigenetic regulation of proteostasis dynamics by the histone methyltransferase complex subunit RBBP5

Article Title: The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics

Article References: Kubra, S., Sun, M., Dion, W., Bian, Y., Catak, A., Luong, H., Wang, H., Pan, Y., Liu, J.-J., Ponna, A., Liu, L., Sipula, I., Luo, J.-H., Jurczak, M. J., Liu, S., & Zhu, B. (2026). The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics. PLOS Biology, 24(10), e3004048. https://doi.org/10.1371/journal.pbio.3004048

Image Credits: AI Generated

DOI: 10.1371/journal.pbio.3004048

Keywords: RBBP5, COMPASS complex, H3K4me3, proteostasis, XBP1s, 12-hour oscillator, ultradian rhythms, autophagy, proteotoxic stress, chromatin, SWI/SNF, Integrator complex