Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation

Abstract

Differentiation of progenitor cells into post-mitotic neurons requires the engagement of mechanisms by which the repressive effects of the neuronal silencer, RE-1 silencing transcription factor (REST), can be overcome1,2. Previously, we described a high-mobility group (HMG)-containing protein, BRAF35, which is a component of a co-repressor complex that is required for the repression of REST-responsive genes3. Here, we show that the BRAF35 family member inhibitor of BRAF35 (iBRAF) activates REST-responsive genes through the modulation of histone methylation. In contrast to BRAF35, iBRAF expression leads to the abrogation of REST-mediated transcriptional repression and the resultant activation of neuronal-specific genes. Analysis of P19 cells during neuronal differentiation revealed an increased concentration of iBRAF at the promoter of neuronal-specific genes coincident with augmented expression of synapsin, recruitment of the methyltransferase MLL and enhanced trimethylation of histone H3 lysine 4 (H3K4). Importantly, ectopic expression of iBRAF is sufficient to induce neuronal differentiation through recruitment of MLL, resulting in increased histone H3K4 trimethylation and activation of neuronal-specific genes. Moreover, depletion of iBRAF abrogates recruitment of MLL and enhancement of histone H3K4 trimethylation. Together, these results indicate that the HMG-domain protein iBRAF has a key role in the initiation of neuronal differentiation.

Cite this article

Wynder, C., Hakimi, MA., Epstein, J. et al. Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation. Nat Cell Biol 7, 1113–1117 (2005). https://doi.org/10.1038/ncb1312

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