Arginine methylation of C/EBP⍺ controls the speed of immune cell transdifferentiation (ChIP-Seq)

C/EBPα is a potent inducer of lymphoid to myeloid cell transdifferentiation. Here we describe that Carm1 methylates arginine 35 in the transactivation domain of C/EBPα, modulating the factor’s activity. Inhibition of methylation or mutation of R35 dramatically enhances the capacity of C/EBPα to induce a B cell-to-macrophage conversion through accelerated chromatin remodeling and subsequent upregulation of myeloid genes and downregulation of B cell genes. This phenomenon is mediated by an increased interaction of unmethylated C/EBPα with the bi-lineage transcription factor PU.1, resulting in the accelerated relocation of PU.1 from B cell to myeloid gene regulatory elements and thus enhancing chromatin remodeling. Our data suggests that C/EBPα effectively converts PU.1 from a B cell to a myeloid regulator through a ‘stealing’ process, and that methylation of C/EBPα by Carm1 modulates this interaction. We propose that individual cells display a pool of methylated and unmethylated C/EBPα, and the proportion of the two molecular forms determines the velocity of cell fate conversion. Study of C/EBPa and PU.1 binding in B cells induced for 3 hours with C/EBPa WT or mutant (R35A)