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

Nature Cell Biology volume 7, pages 1113–1117 (2005)Cite this article

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.

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Figure 1: iBRAF and BRAF35 display opposing expression patterns during neurogenesis.
Figure 2: iBRAF activates synapsin and Neurod2 gene expression.
Figure 3: Recruitment of iBRAF and MLL to the RE-1 element during neural differentiation.
Figure 4: iBRAF promotes neuronal differentiation.

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Acknowledgements

R.S. was funded by a grant from the National Institutes of Health (GM 61204).

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Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce St., Philadelphia, 19104, PA, USA

    Christopher Wynder & Ramin Shiekhattar

  2. CNRS, UMR5163, Université Joseph Fourier, La Tronche, 38700, France

    Mohamed-Ali Hakimi

  3. Cardiovascular Institute, School of Medicine, University of Pennsylvania, 954 BRB II, Philadelphia, 19104, PA, USA

    Jonathan A. Epstein

  4. Department of Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, St. Louis, 63108, MO, USA

    Ali Shilatifard

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Correspondence to Ramin Shiekhattar.

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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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