{
  "abstract": "Proteostasis is essential for cellular health, with its disruption contributing to aging, neurodegeneration, and metabolic disorders. While the upstream proteotoxic 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, proteotoxic 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 an 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. In contrast, histone acetyltransferases and H3K9 acetylation were dispensable for dynamic proteostasis gene expression. RBBP5 is not only indispensable for the 12-hour oscillator but also essential for the transcriptional regulation of diverse proteotoxic stresses response, by coactivating XBP1s and promoting H3K4me3 deposition at the promoters of proteostasis genes. As a result, loss of RBBP5 sensitizes cells to proteotoxic stress in part due to impaired autophagy. Proximity labeling of H3K4me3 further uncovered a dynamic chromatin-associated proteomic architecture, including components of COMPASS, the Integrator complex and SWI/SNF remodelers, that constitutes the transcriptional response to proteotoxic stress. Together, these findings establish RBBP5 as a central regulator of proteostasis dynamics, essential for maintaining cellular resilience.\n\nProteostasis is essential for cellular health, but the epigenetic mechanisms regulating dynamic proteostasis programs are poorly understood. This study shows that RBBP5, a subunit of the COMPASS histone methyltransferase complex, controls ultradian proteostasis gene expression by promoting H3K4me3 deposition at the promoters of proteostasis genes.",
  "abstract_shown": true,
  "affiliations": [
    "Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.",
    "UPMC Genome Center, UPMC, Pittsburgh, Pennsylvania, United States of America.",
    "Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.",
    "Organ Pathobiology and Therapeutics Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.",
    "Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.",
    "Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.",
    "Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.",
    "Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Syeda Kubra"
    },
    {
      "affs": [
        0
      ],
      "name": "Michelle Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "William Dion"
    },
    {
      "affs": [
        0
      ],
      "name": "Yu Bian"
    },
    {
      "affs": [
        0
      ],
      "name": "Ahmet Catak"
    },
    {
      "affs": [
        0
      ],
      "name": "Hannah Luong"
    },
    {
      "affs": [
        0
      ],
      "name": "Haokun Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yinghong Pan"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Jia-Jun Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Aishwarya Ponna"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Lijun Liu"
    },
    {
      "affs": [
        5
      ],
      "name": "Ian Sipula"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Jian-Hua Luo"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Michael J Jurczak"
    },
    {
      "affs": [
        2,
        3,
        7
      ],
      "name": "Silvia Liu"
    },
    {
      "affs": [
        0,
        2,
        5
      ],
      "name": "Bokai Zhu",
      "orcid": "0000-0003-0827-5757"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/39d1cecx0v0jv.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pbio.3004048",
  "fulltext_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004048",
  "id": "39d1cecx0v0jv",
  "issns": [
    "1545-7885",
    "1544-9173"
  ],
  "landing_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004048",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
    ],
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      "plos",
      "/Biology and life sciences/Biochemistry/Circadian oscillators"
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      "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Non-coding RNA/Small interfering RNA"
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      "plos",
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    [
      "plos",
      "/Biology and life sciences/Chronobiology/Circadian rhythms"
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      "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Small interfering RNA"
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    [
      "plos",
      "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Transcriptional control"
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      "/Biology and life sciences/Genetics/Genetic oscillators"
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      "/Biology and life sciences/Genetics/Genomics/Genome analysis/Transcriptome analysis"
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  "pdf_url": "https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3004048&type=printable",
  "pmcid": "PMC13667922",
  "pmid": "42848836",
  "published": "2026-10-08",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/39d1cecx0v0jv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.pbio.3004048",
      "source": "plos",
      "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004048"
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    {
      "first_seen": "2026-10-30T12:18:02Z",
      "native_id": "MED:42848836",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42848836"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:gene expression",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics",
  "title_text": "The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:02Z",
  "url": "https://research.draconitic.com/paper/39d1cecx0v0jv",
  "venue": "PLOS Biology",
  "versions": []
}