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

Wynder, Christopher; Hakimi, Mohamed‐Ali; Epstein, Jonathan A.; Shilatifard, Ali; Shiekhattar, Ramin

doi:10.1038/ncb1312

Cited by 80 publications

(93 citation statements)

References 19 publications

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“…As BRAF35, iBRAF contains an HMG domain in its amino terminus and a coiled-coil domain in the carboxyl-terminal half of the protein. In the mouse developing brain, Braf35 is predominantly expressed in immature neurons at the edges of the ventricles whereas iBraf is expressed in mature neurons, with the highest level being present in the outer cortex (13). Consistent with this expression pattern it has been shown that iBRAF improves neuronal differentiation of P19 cells.…”

supporting

confidence: 57%

“…iBraf was described as an antagonist of Braf35 during neuronal differentiation, based on the fact that iBraf recruits the H3K4 methyltransferase MLL to neuronal specific genes (13). Now we show that iBraf can form homodimers and heterodimers with Braf35.…”

Section: Discussionmentioning

confidence: 92%

“…Furthermore, iBRAF activates expression of neuronal specific genes, whereas BRAF35 represses neuronal specific genes. Wynder et al showed that iBRAF promotes recruitment of the histone methyltransferase MLL to neuronal specific genes (13). However, the molecular mechanism by which iBRAF antagonizes BRAF35 activity was unclear.…”

mentioning

confidence: 99%

“…iBRAF (inhibitor of BRAF35, also called HMG20A) is a close paralogue of BRAF35 (13). As BRAF35, iBRAF contains an HMG domain in its amino terminus and a coiled-coil domain in the carboxyl-terminal half of the protein.…”

mentioning

confidence: 99%

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Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex

Ceballos-Chávez

Rivero

García-Gutiérrez³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The LSD1-CoREST histone demethylase complex is required to repress neuronal genes in nonneuronal tissues. Here we show that sumoylation of Braf35, one of the subunits of the complex, is required to maintain full repression of neuron-specific genes and for occupancy of the LSD1-CoREST complex at its gene targets. Interestingly, expression of Braf35 was sufficient to prevent neuronal differentiation induced by bHLH neurogenic transcription factors in P19 cells and in neuronal progenitors of the chicken embryo neural tube. Sumoylation of Braf35 is required for this antineurogenic activity. We also show that iBraf, a paralogue of Braf35, forms heterodimers with Braf35. Braf35-iBraf heterodimerization impairs Braf35 interaction with the LSD1-CoREST complex and inhibits Braf35 sumoylation. Consistent with these results, iBraf prevents the antineurogenic activity of Braf35 in vivo. Our data uncover a mechanism of regulation of the LSD1-CoREST complex and provide a molecular explanation for the antagonism between Braf35 and iBraf in neuronal differentiation.C ell differentiation involves large modifications of gene expression that require extensive changes of chromatin epigenetic marks (1). Epigenetic marks are DNA or histone posttranslational modifications that are inherited through cell division and that inform about the transcriptional state of loci. Among histone modifications, histone lysine methylation is of particular interest in development for the broad range of processes in which it is involved, including maintenance of stem cell pluripotency, germ-line determination, cell differentiation, control of HOX genes expression, and so forth (2, 3). Histone lysine methylation was considered a stable posttranslational modification until the discovery of histone demethylases. LSD1/KDM1 (lysine-specific demethylase 1) was the first demethylase identified and catalyzes demethylation of both di-and monomethylated lysine 4 (K4) or lysine 9 (K9) of histone H3 (H3K4me2/1 or H3K9me2/1) (4, 5). The lysine specificity of LSD1 seems to depend on its molecular partners. Thus, when LSD1 is associated with CoREST in the LSD1-CoREST corepressor complex (also called BHC, BRAF-histone deacetylase complex), the preferred substrate is H3K4me2/1, consistent with the fact that methylation of H3K4 is a mark of transcriptionaly active genes. In addition to LSD1 and CoREST, the LSD1-CoREST complex also contains HDAC1-2, BHC80, and BRAF35 (also called HMG20B) (6-9). BRAF35 contains a high-mobility group (HMG) domain and a coiled-coil domain, but its function within the complex is not well-understood (7, 10). Several functions of the LSD1-CoREST complex in differentiation and development have been reported (2). One of the best-characterized functions of the complex is its role in repression of neuronal genes in nonneuronal tissues and neuronal progenitors through its interaction with repressor factor REST (RE1 silencing transcription factor) (11,12). iBRAF (inhibitor of BRAF35, also called HMG20A) is a close paralogue of BRAF35 (13). As BRAF35...

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supporting

confidence: 57%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex

Ceballos-Chávez

Rivero

García-Gutiérrez³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, the BRAF35 homologue, an inhibitor of BRAF35 (iBRAF), has been shown to activate REST/NRSFregulated genes through the modulation of histone methylation (Wynder et al 2005). Analysis of mouse embryonic carcinoma P19 cells undergoing neuronal differentiation revealed iBRAF accumulation at the promoter of neuron-specific genes coincident with the augmented expression of neuron-specific synapsin, recruitment of the H3K4 methyltransferase mixedlineage leukaemia (MLL) and enhanced trimethylation of H3K4.…”

Section: Histone Modification and Neural Differentiationmentioning

confidence: 99%

Epigenetic mechanisms regulating fate specification of neural stem cells

Namihira

Kohyama

Abematsu

et al. 2008

Phil. Trans. R. Soc. B

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Neural stem cells (NSCs) possess the ability to self-renew and to differentiate along neuronal and glial lineages. These processes are defined by the dynamic interplay between extracellular cues including cytokine signalling and intracellular programmes such as epigenetic modification. There is increasing evidence that epigenetic mechanisms involving, for example, changes in DNA methylation, histone modification and non-coding RNA expression are closely associated with fate specification of NSCs. These epigenetic alterations could provide coordinated systems for regulating gene expression at each step of neural cell differentiation. Here we review the roles of epigenetics in neural fate specification in the mammalian central nervous system.

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