Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity
Authors
- G. Torcal Garcia
- E. Kowenz-Leutz
- T.V Tian
- A. Klonizakis
- J. Lerner
- L. De Andres-Aguayo
- V. Sapozhnikova
- C. Berenguer
- M.P. Carmona
- M.V. Casadesus
- R. Bulteau
- M. Francesconi
- S. Peiro
- P. Mertins
- K. Zaret
- A. Leutz
- T. Graf
Journal
- eLife
Citation
- eLife 12: e83951
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/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.