1. Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity.
- Author
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Garcia, Guillem Torcal, Kowenz-Leutz, Elisabeth, Tian, Tian V., Klonizakis, Antonis, Lerner, Jonathan, De Andres-Aguayo, Luisa, Sapozhnikova, Valeriia, Berenguer, Clara, Carmona, Marcos Plana, Casadesus, Maria Vila, Bulteau, Romain, Francesconi, Mirko, Peiro, Sandra, Mertins, Philipp, Zaret, Kenneth, Leutz, Achim, and Graf, Thomas
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TRANSCRIPTION factors , *B cells , *MACROPHAGE activation , *VELOCITY , *METHYLATION , *CELL differentiation - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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