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PreprintCited by 64Genomics and Chromatin DynamicsProtein Degradation and InhibitorsChromatin Remodeling and Cancer

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Structural insights into p300 regulation and acetylation-dependent genome organisation

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Ibrahim, Ziad, Wang, Tao, Destaing, Olivier, Salvi, Nicola, Hoghoughi, Naghmeh, Chabert, Clovis, Rusu, Alexandra, Gao, Jinjun, Feletto, Leonardo, Reynoird, Nicolas, Schalch, Thomas, Zhao, Yingming, Blackledge, Martin, Khochbin, Saadi, Panne, Daniel·2022·Nature Communications
DOI 10.1101/2022.03.14.484228PMC PMC9755262

Preprint — published as 10.1038/s41467-022-35375-2 · Paper page

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Abstract

Summary: 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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Metadata

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
Publisher
openRxiv
Published
2022-03-14
Volume
13
Issue
1
Pages
7759-7759
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2022.03.14.484228
PMC
PMC9755262
OpenAlex
W4312224088
Cited by
64
References
1
Citations by year
2026: 16 · 2025: 15 · 2024: 14 · 2023: 17 · 2022: 1
FWCI
4.08
Type
journal article
Language
en
Open access
Licence
cc-by
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 (18571, 221881, 221881/Z/20/Z)
  • Worldwide Cancer Research (16-0280)
  • Diamond Light Source
  • Université Grenoble Alpes (ANR-10-INBS-0005-02, ANR‐17‐EURE‐0003, ANR-15-IDEX-02)
  • Alliance Nationale pour les Sciences de la Vie et de la Santé
  • Agence Nationale de la Recherche (UAR 3518 CNRS-CEA-UGA-EMBL, ANR-17-EURE-0003, ANR-19-CE12-0014, IDEX-02, ANR-17-EURE-, ANR‐15‐IDEX‐02, ANR-15-IDEX-02 SYMER, ANR-17, ANR-10, ANR-10-INBS-0005, 15-IDEX-02)
  • Fondation ARC pour la Recherche sur le Cancer (RF20190208471)
  • Centre National de la Recherche Scientifique (ANR‐17‐EURE‐0003, UAR 3518 CNRS-CEA-UGA-EMBL)
  • French Infrastructure for Integrated Structural Biology (ANR-15-IDEX-02, ANR-17-EURE-0003, ANR-10-INBS-0005, ANR-10-INBS-000502, ANR-10-INBS)
  • Medical Research Council (MR/W001667/1, MC_PC_17136)
  • Biotechnology and Biological Sciences Research Council (BB/S019510/1, BB/R016275/1, UAR 3518 CNRS-CEA-UGA-EMBL)
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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