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

Citació

  • 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

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Descripció

  • Resum

    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.
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