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| Item Type: | Article |
|---|---|
| Title: | Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity |
| Creators: |
Torcal Garcia, G.  ORCID: https://orcid.org/0000-0002-0843-7296, Kowenz-Leutz, E., Tian, T.V ORCID: https://orcid.org/0000-0002-9906-0980, Klonizakis, A., Lerner, J., De Andres-Aguayo, L., Sapozhnikova, V., Berenguer, C., Carmona, M.P., Casadesus, M.V., Bulteau, R. ORCID: https://orcid.org/0000-0002-9128-8809, Francesconi, M., Peiro, S., Mertins, P. ORCID: https://orcid.org/0000-0002-2245-528X, Zaret, K., Leutz, A. ORCID: https://orcid.org/0000-0001-8259-927X and Graf, T. ORCID: https://orcid.org/0000-0003-2774-4117
|
| 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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