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

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dc.contributor.authorIsbel, L.
dc.contributor.authorIskar, M.
dc.contributor.authorDurdu, S.
dc.contributor.authorWeiss, J.
dc.contributor.authorGrand, R.S.
dc.contributor.authorHietter-Pfeiffer, E.
dc.contributor.authorKozicka, Z.
dc.contributor.authorMichael, A.K.
dc.contributor.authorBurger, L.
dc.contributor.authorThomä, N.H.
dc.contributor.authorSchübeler, D.
dc.date.issued2023
dc.description.abstractThe 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.
dc.description.statementofresponsibilityLuke Isbel, Murat Iskar, Sevi Durdu, Joscha Weiss, Ralph S. Grand, Eric Hietter-Pfeiffer, Zuzanna Kozicka, Alicia K. Michael, Lukas Burger, Nicolas H. Thomä, Dirk Schübeler
dc.identifier.citationNature Structural and Molecular Biology, 2023; 30(7):948-957
dc.identifier.doi10.1038/s41594-023-01021-8
dc.identifier.issn1545-9993
dc.identifier.issn1545-9985
dc.identifier.orcidIsbel, L. [0000-0002-5270-4347]
dc.identifier.urihttps://hdl.handle.net/2440/139184
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1148380
dc.rights© The Author(s) 2023 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41594-023-01021-8
dc.subjectChromatin
dc.subjectHistones
dc.subjectTranscription Factors
dc.subjectDNA Methylation
dc.subjectProtein Processing, Post-Translational
dc.subjectTumor Suppressor Protein p53
dc.subject.meshChromatin
dc.subject.meshHistones
dc.subject.meshTranscription Factors
dc.subject.meshDNA Methylation
dc.subject.meshProtein Processing, Post-Translational
dc.subject.meshTumor Suppressor Protein p53
dc.titleReadout of histone methylation by Trim24 locally restricts chromatin opening by p53.
dc.typeJournal article
pubs.publication-statusPublished

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