PT  - JOURNAL ARTICLE
AU  - Guillem Torcal Garcia
AU  - Elisabeth Kowenz-Leutz
AU  - Tian V. Tian
AU  - Antonios Klonizakis
AU  - Jonathan Lerner
AU  - Luisa de Andrés-Aguayo
AU  - Clara Berenguer
AU  - Marcos Plana-Carmona
AU  - Maria Vila-Casadesús
AU  - Romain Bulteau
AU  - Mirko Francesconi
AU  - Sandra Peiró
AU  - Kenneth S. Zaret
AU  - Achim Leutz
AU  - Thomas Graf
TI  - Carm1 regulates the speed of C/EBPα-induced transdifferentiation by a cofactor stealing mechanism
AID  - 10.1101/2022.10.03.510647
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.03.510647
4099  - http://biorxiv.org/content/early/2022/10/04/2022.10.03.510647.1.short
4100  - http://biorxiv.org/content/early/2022/10/04/2022.10.03.510647.1.full
AB  - Cell fate decisions are driven by lineage-restricted transcription factors but how they are regulated is incompletely understood. The C/EBPα-induced B cell to macrophage transdifferentiation (BMT) is a powerful system to address this question. Here we describe that C/EBPα with a single arginine mutation (C/EBPαR35A) induces a dramatically accelerated BMT in mouse and human cells. Changes in the expression of lineage-restricted genes occur as early as within 1 hour compared to 18 hours with the wild type. Mechanistically C/EBPαR35A exhibits an increased affinity for PU.1, a bi-lineage transcription factor required for C/EBPα-induced BMT. The complex induces more rapid chromatin accessibility changes and an enhanced relocation (stealing) of PU.1 from B cell to myeloid gene regulatory elements. Arginine 35 is methylated by Carm1 and inhibition of the enzyme accelerates BMT, similar to the mutant. Our data suggest that the relative proportions of methylated and unmethylated C/EBPα in bipotent progenitors determine the velocity of cell fate choice and also affect lineage directionality. The PU.1 stealing mechanism described can explain how the faithfulness of a cell fate conversion is maintained even when its velocity varies.Competing Interest StatementThe authors have declared no competing interest.