Structure and functional studies of HDAC complexes

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Class-1 histone deacetylases (HDACs 1, 2, 3) are essential enzymes present in the nucleus of all mammalian cells, where they help regulate chromatin structure as the catalytic component of large multi-protein co-repressor complexes such as Sin3A/B, NuRD, CoREST, MIDAC and NCoR/SMRT. Each of these complexes is recruited to target genes by specific transcription factors to regulate transcription. Incorporation into specific complexes is fundamental to HDAC 1, 2 and 3 function since this directs both substrate specificity as well as regulating the enzymatic activity of the HDAC. Histone deacetylase enzymes (HDACs) are generally thought to regulate gene expression by removing acetyl groups from lysine residues in histone tails resulting in chromatin condensation and gene repression, although gene profiling has shown HDACs are predominately located at active genes, suggesting a role in resetting chromatin between rounds of transcription.This PhD project will involve using structural biology techniques to investigate the assembly and chromatin interactions of the NuRD and CoREST complexes with a view to determining their detailed mechanism of action. The research will involve both structural and functional approaches and will utilise X-ray crystallography, cryo-electron microscopy as well as biophysical and cell biology techniques.