TY - JOUR
T1 - Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation
AU - Wynder, Christopher
AU - Hakimi, Mohamed Ali
AU - Epstein, Jonathan A.
AU - Shilatifard, Ali
AU - Shiekhattar, Ramin
PY - 2005/11
Y1 - 2005/11
N2 - 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 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, 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.
AB - 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 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, 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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U2 - 10.1038/ncb1312
DO - 10.1038/ncb1312
M3 - Article
C2 - 16227968
AN - SCOPUS:33644823190
SN - 1465-7392
VL - 7
SP - 1113
EP - 1117
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 11
ER -