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

• Published in: eLife 2023-06, 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: Article
• Language: English
• Subjects: Animal models; Animals; blood cell differentiation; CCAAT-Enhancer-Binding Protein-alpha - genetics; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cell activation; Cell differentiation; Cell Differentiation - genetics; Cell fate; Cell Transdifferentiation; Chromatin; Developmental Biology; DNA methylation; Enhancers; Gene expression; gene regulation; Humans; Leukocytes (granulocytic); lineage choice; Lymphocytes B; Macrophages; Methylation; Mice; Mutants; Mutation; Ontology; Principal components analysis; Proto-Oncogene Proteins - metabolism; PU.1 protein; Statistical significance; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription activation; transcription factor; transdifferentiation; Velocity
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.83951

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 ) 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/EBPα , 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.