Carm1-arginine methylation of the transcription factor C/EBP[alpha] regulates transdifferentiation velocity

• Published in: eLife Vol. 12
• Main Authors: Torcal Garcia, Guillem, 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, Graf, Thomas
• Format: Journal Article
• Language: English
• Published: eLife Science Publications, Ltd 27-06-2023
• Subjects: Analysis; Arginine; B cells; Chromatin; Macrophages; Methylation; Scientific equipment and supplies industry; United States
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.83951

Here, we describe how the speed of C/EBP[alpha]-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBP[alpha] (C/EBP[alpha].sup.R35A) that greatly accelerates BMT helped to illuminate the mechanism. Thus, incoming C/EBP[alpha] 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/EBP[alpha], causing chromatin opening and activation of macrophage genes. All these steps are accelerated by C/EBP[alpha].sup.R35A, initiated by its increased affinity for PU.1. Wild-type C/EBP[alpha] 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/EBP[alpha] 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.