| Autor: |
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. |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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