A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes.
BRAF35, a structural DNA-binding protein, initially was identified as a component of a large BRCA2-containing complex. Biochemical analysis revealed the presence of a smaller core-BRAF35 complex devoid of BRCA2. Here we report the isolation of a six-subunit core-BRAF35 complex with the capacity to deacetylate histones, termed the BRAF-histone deacetylase complex (BHC), from human cells. BHC contains polypeptides reminiscent of the chromatin-remodeling complexes SWI/SNF and NuRD (nucleosome remodeling and deacetylating). Similar to NuRD, BHC contains an Mi2-like subunit, BHC80, and a PHD zinc-finger subunit as well as histone deacetylases 1/2 and an MTA-like subunit, the transcriptional corepressor CoREST. We show that BHC mediates repression of neuron-specific genes through the cis-regulatory element known as the repressor element 1 or neural restrictive silencer (RE1/NRS). Chromatin-immunoprecipitation experiments demonstrate the recruitment of BHC by the neuronal repressor REST. Expression of BRAF35 containing a single point mutation in the HMG domain of the protein abrogated REST-mediated transcriptional repression. These results demonstrate a role for core-BRAF35-containing complex in the regulation of neuron-specific genes through modulation of the chromatin structure.
Hakimi
Mohamed-Ali
MA
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Bochar
Daniel A
DA
Chenoweth
Josh
J
Lane
William S
WS
Mandel
Gail
G
Shiekhattar
Ramin
R
D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D002852:Chromatography, Ion Exchange; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006609:High Mobility Group Proteins; D006655:Histone Deacetylases / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D021122:Protein Subunits; D012097:Repressor Proteins / Q000378:metabolism*; D016704:Synapsins / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D016335:Zinc Fingers
D002843:Chromatin; D004268:DNA-Binding Proteins; C000625244:HMG20B protein, human; D006609:High Mobility Group Proteins; D021122:Protein Subunits; D012097:Repressor Proteins; D016704:Synapsins; D006655:Histone Deacetylases