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

Nat Cell Biol. 2005 Nov;7(11):1113-7. doi: 10.1038/ncb1312.


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 overcome. 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 genes. 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, iBRAFexpression 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / embryology*
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • High Mobility Group Proteins / physiology*
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Methylation
  • Mice
  • Neurons / physiology*
  • Protein Methyltransferases
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Synapsins / genetics
  • Transcription Factors / physiology
  • Transfection
  • Tumor Cells, Cultured


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Histones
  • Hmg20a protein, mouse
  • Hmg20b protein, mouse
  • Synapsins
  • Transcription Factors
  • Histone Methyltransferases
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf