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

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Item Type:Article
Title:Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity
Creators Name:Torcal Garcia, G. and Kowenz-Leutz, E. and Tian, T.V and Klonizakis, A. and Lerner, J. and De Andres-Aguayo, L. and Sapozhnikova, V. and Berenguer, C. and Carmona, M.P. and Casadesus, M.V. and Bulteau, R. and Francesconi, M. and Peiro, S. and Mertins, P. and Zaret, K. and Leutz, A. and Graf, T.
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/EBPα(R35A)) 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.
Keywords:CCAAT-Enhancer-Binding Protein-alpha, Cell Differentiation, Cell Transdifferentiation, Chromatin, Methylation, Proto-Oncogene Proteins, Trans-Activators, Animals, Mice
Publisher:eLife Sciences Publications
Page Range:e83951
Date:27 June 2023
Official Publication:https://doi.org/10.7554/eLife.83951
PubMed:View item in PubMed

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