Readout of histone methylation by Trim24 locally restricts chromatin opening by p53.


Journal

Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374

Informations de publication

Date de publication:
07 2023
Historique:
received: 23 06 2022
accepted: 15 05 2023
medline: 19 7 2023
pubmed: 30 6 2023
entrez: 29 6 2023
Statut: ppublish

Résumé

The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually diverse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated histone 3 lysine 4 (H3K4), thereby preferentially localizing to those p53 sites that reside in closed chromatin, whereas it is deterred from accessible chromatin by H3K4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to affect gene expression as a function of the local chromatin state. These findings link H3K4 methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors that locally modulate TF function.

Identifiants

pubmed: 37386214
doi: 10.1038/s41594-023-01021-8
pii: 10.1038/s41594-023-01021-8
pmc: PMC10352137
doi:

Substances chimiques

Chromatin 0
Histones 0
Tumor Suppressor Protein p53 0
Transcription Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

948-957

Informations de copyright

© 2023. The Author(s).

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Auteurs

Luke Isbel (L)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.

Murat Iskar (M)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Sevi Durdu (S)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Joscha Weiss (J)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Faculty of Sciences, University of Basel, Basel, Switzerland.

Ralph S Grand (RS)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany.

Eric Hietter-Pfeiffer (E)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Faculty of Sciences, University of Basel, Basel, Switzerland.

Zuzanna Kozicka (Z)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Faculty of Sciences, University of Basel, Basel, Switzerland.

Alicia K Michael (AK)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Biozentrum, University of Basel, Basel, Switzerland.

Lukas Burger (L)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Swiss Institute of Bioinformatics, Basel, Switzerland.

Nicolas H Thomä (NH)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Dirk Schübeler (D)

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. dirk@fmi.ch.
Faculty of Sciences, University of Basel, Basel, Switzerland. dirk@fmi.ch.

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Classifications MeSH