Author response: Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity
Year: 2023
Type: peer-review
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/EBPα R35A , 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. Editor's evaluationThis important manuscript describes how the methylation of a single arginine residue in a transcription factor, C/EBPα, can alter the dynamics of cell fate transition.The study provides one of the most striking examples of transcription factor regulation by methylation and is well-executed, with compelling evidence to support the authors' claims.These findings substantially advance our understanding of a major research question.
Authors: Guillem Torcal Garcia, Elisabeth Kowenz-Leutz, Tian V Tian, Antonis Klonizakis, Jonathan Lerner, Luisa De Andres-Aguayo, Valeriia Sapozhnikova, Clara Berenguer, Marcos Plana Carmona, Maria Vila Casadesus, Romain Bulteau, Mirko Francesconi, Sandra Peiro, Philipp Mertins, Kenneth Zaret, Achim Leutz, Thomas Graf
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Awards: G653594597, G9000165828
OpenAlex ID: W4382461561