Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation.
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.
Wynder
Christopher
C
The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA.
Hakimi
Mohamed-Ali
MA
Epstein
Jonathan A
JA
Shilatifard
Ali
A
Shiekhattar
Ramin
R
D000818:Animals; D001921:Brain / Q000196:embryology*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins / Q000502:physiology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009474:Neurons / Q000502:physiology*; D011496:Protein Methyltransferases; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D016704:Synapsins / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D006657:Histones; C507322:Hmg20a protein, mouse; C400291:Hmg20b protein, mouse; D016704:Synapsins; D014157:Transcription Factors; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf