Torcal Garcia, Guillem, 1991-Kowenz-Leutz, ElisabethTian, Tian V.Klonizakis, AntoniosLerner, JonathanAndrés Aguayo, Luisa deSapozhnikova, ValeriiaBerenguer, ClaraPlana Carmona, Marcos, 1993-Vila-Casadesús, MariaBulteau, RomainFrancesconi, MirkoPeiró Sales, SandraMertins, PhilippZaret, Kenneth S.Leutz, AchimGraf, T. (Thomas)2023-10-302023-10-302023Torcal 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.839512050-084Xhttp://hdl.handle.net/10230/58178Here, 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/eLife.83951Blood cell differentiationCell fateDevelopmental biologyGene regulationLineage choiceMouseTranscription factorTransdifferentiationinfo:eu-repo/semantics/openAccess