Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity

Torcal Garcia, Guillem, 1991-; Kowenz-Leutz, Elisabeth; Tian, Tian V.; Klonizakis, Antonios; Lerner, Jonathan; Andrés Aguayo, Luisa de; Sapozhnikova, Valeriia; Berenguer, Clara; Plana Carmona, Marcos, 1993-; Vila-Casadesús, Maria; Bulteau, Romain; Francesconi, Mirko; Peiró Sales, Sandra; Mertins, Philipp; Zaret, Kenneth S.; Leutz, Achim; Graf, T. (Thomas)

Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity

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dc.contributor.author Torcal Garcia, Guillem, 1991-
dc.contributor.author Kowenz-Leutz, Elisabeth
dc.contributor.author Tian, Tian V.
dc.contributor.author Klonizakis, Antonios
dc.contributor.author Lerner, Jonathan
dc.contributor.author Andrés Aguayo, Luisa de
dc.contributor.author Sapozhnikova, Valeriia
dc.contributor.author Berenguer, Clara
dc.contributor.author Plana Carmona, Marcos, 1993-
dc.contributor.author Vila-Casadesús, Maria
dc.contributor.author Bulteau, Romain
dc.contributor.author Francesconi, Mirko
dc.contributor.author Peiró Sales, Sandra
dc.contributor.author Mertins, Philipp
dc.contributor.author Zaret, Kenneth S.
dc.contributor.author Leutz, Achim
dc.contributor.author Graf, T. (Thomas)
dc.date.accessioned 2023-10-30T07:07:54Z
dc.date.available 2023-10-30T07:07:54Z
dc.date.issued 2023
dc.description.abstract Here, we describe how the speed of C/EBPα-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBPα (C/EBPαR35A) that greatly accelerates BMT helped to illuminate the mechanism. Thus, incoming C/EBPα binds to PU.1, an obligate partner expressed in B cells, leading to the release of PU.1 from B cell enhancers, chromatin closing and silencing of the B cell program. Released PU.1 redistributes to macrophage enhancers newly occupied by C/EBPα, causing chromatin opening and activation of macrophage genes. All these steps are accelerated by C/EBPαR35A, initiated by its increased affinity for PU.1. Wild-type C/EBPα is methylated by Carm1 at arginine 35 and the enzyme's perturbations modulate BMT velocity as predicted from the observations with the mutant. Increasing the proportion of unmethylated C/EBPα in granulocyte/macrophage progenitors by inhibiting Carm1 biases the cell's differentiation toward macrophages, suggesting that cell fate decision velocity and lineage directionality are closely linked processes.
dc.description.sponsorship We thank the Graf laboratory members for critical discussions, the Flow Cytometry and Microscopy unit of UPF-CRG for technical assistance, the CRG Genomics core facility for sequencing and Lars Velten for feedback on the manuscript. TG was supported by the Center for Genomic Regulation, Barcelona, the Spanish Ministry of Economy, Industry and Competitiveness, (Plan Estatal PID2019-109354GB-100), AGAUR (SGR 006713) and the 4D-Genome European Research Council Synergy grant. KSZ was supported by the NIH grant R01GM36477. We have used ChatGPT to improve parts of the text.
dc.format.mimetype application/pdf
dc.identifier.citation Torcal Garcia G, Kowenz-Leutz E, Tian TV, Klonizakis A, Lerner J, De Andres-Aguayo L, Sapozhnikova V, Berenguer C, Carmona MP, Casadesus MV, Bulteau R, Francesconi M, Peiro S, Mertins P, Zaret K, Leutz A, Graf T. Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity. Elife. 2023 Jun 27;12:e83951. DOI: 10.7554/eLife.83951
dc.identifier.doi http://dx.doi.org/10.7554/eLife.83951
dc.identifier.issn 2050-084X
dc.identifier.uri http://hdl.handle.net/10230/58178
dc.language.iso eng
dc.publisher eLife
dc.relation.ispartof Elife. 2023 Jun 27;12:e83951
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-109354GB-100
dc.rights © 2023, Torcal Garcia, Kowenz-Leutz, Tian et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Blood cell differentiation
dc.subject.keyword Cell fate
dc.subject.keyword Developmental biology
dc.subject.keyword Gene regulation
dc.subject.keyword Lineage choice
dc.subject.keyword Mouse
dc.subject.keyword Transcription factor
dc.subject.keyword Transdifferentiation
dc.title Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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