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

Torcal Garcia, G.; Kowenz-Leutz, E.; Tian, T.V; Klonizakis, A.; Lerner, J.; De Andres-Aguayo, L.; Sapozhnikova, V.; Berenguer, C.; Carmona, M.P.; Casadesus, M.V.; Bulteau, R.; Francesconi, M.; Peiro, S.; Mertins, P.; Zaret, K.; Leutz, A.; Graf, T.

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

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Item Type:	Article
Title:	Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity
Creators Name:	Torcal Garcia, G., Kowenz-Leutz, E., Tian, T.V, Klonizakis, A., Lerner, J., De Andres-Aguayo, L., Sapozhnikova, V., Berenguer, C., Carmona, M.P., Casadesus, M.V., Bulteau, R., Francesconi, M., Peiro, S., Mertins, P., Zaret, K., Leutz, A. and Graf, T.
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.
Keywords:	CCAAT-Enhancer-Binding Protein-alpha, Cell Differentiation, Cell Transdifferentiation, Chromatin, Methylation, Proto-Oncogene Proteins, Trans-Activators, Animals, Mice
Source:	eLife
ISSN:	2050-084X
Publisher:	eLife Sciences Publications
Volume:	12
Page Range:	e83951
Date:	27 June 2023
Official Publication:	https://doi.org/10.7554/eLife.83951
PubMed:	View item in PubMed

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