Structural insights into p300 regulation and acetylation-dependent genome organisation
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Abstract
Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of the acetyl lysine reader BRD4 that binds to the acetylase p300 and enables formation of long-range intra- and interchromosomal interactions. We here examine how acetylation reading and writing enable formation of such interactions. We show that NUT contains an acidic transcriptional activation domain that binds to the TAZ2 domain of p300. We use NMR to investigate the structure of the complex and found that the TAZ2 domain has an autoinhibitory role for p300. NUT-TAZ2 interaction or mutations found in cancer that interfere with autoinhibition by TAZ2 allosterically activate p300. p300 activation results in a self-organizing, acetylation-dependent feed-forward reaction that enables long-range interactions by bromodomain multivalent acetyl-lysine binding. We discuss the implications for chromatin organisation, gene regulation and dysregulation in disease.
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Flagged first, then by citations
- Authors
- Ibrahim, Z., Wang, T., Destaing, O., Salvi, N., Hoghoughi, N., Chabert, C., Rusu, A., Gao, J., Feletto, L., Reynoird, N., Schalch, T., Zhao, Y., Blackledge, M., Khochbin, S., & Panne, D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- University of Leicester (GB)
- University of Chicago (US)
- Corresponding author
- Panne, Daniel
- ORCID
- Venue
- Nature Communications
- Published
- 2022-12-15
- Volume
- 13
- Issue
- 1
- Pages
- 7759-7759
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9755262
- OpenAlex
- W4312224088
- Cited by
- 64
- References
- 15
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 14 · 2023: 17 · 2022: 1
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Chicago (cc-by)
- Funders
- Wellcome Trust (221881/Z/20/Z)
- RCUK | Medical Research Council (MR/W001667/1)
- Worldwide Cancer Research (16-0280)
- Instruct-ERIC [PID: 18571]
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- P300, histone acetylation, autoinhibition, bromodomain, long-range chromatin interactions, chromatin organization, feed-forward activation, fusion oncogenes, gene expression regulation
- MeSH terms
- Acetylation, Chromatin, Lysine, Nuclear Proteins, Transcription Factors
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