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

Author:

Torcal Garcia Guillem12ORCID,Kowenz-Leutz Elisabeth3,Tian Tian V124ORCID,Klonizakis Antonis12,Lerner Jonathan5,De Andres-Aguayo Luisa12,Sapozhnikova Valeriia3,Berenguer Clara12,Carmona Marcos Plana12,Casadesus Maria Vila124,Bulteau Romain6ORCID,Francesconi Mirko6,Peiro Sandra4,Mertins Philipp3,Zaret Kenneth5,Leutz Achim3,Graf Thomas12ORCID

Affiliation:

1. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)

2. Universitat Pompeu Fabra (UPF)

3. Max Delbrück Center for Molecular Medicine in the Helmholtz Association

4. Vall d’Hebron Institute of Oncology (VHIO)

5. Perelman School of Medicine, University of Pennsylvania

6. Laboratorie de Biologie et Modélisation de la Cellule, Université de Lyon

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/EBPαR35A) 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.

Funder

Agència de Gestió d'Ajuts Universitaris i de Recerca

National Institutes of Health

Spanish Ministry of Economy, Industry and Competitiveness

European Research Council

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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