Understanding the diverse molecular mechanisms of chromatin-targeted histone deacetylase complexes

Eukaryotic gene regulation depends upon a plethora of multi-protein complexes that both control the organisation of chromatin and establish specific patterns of post-translational modifications of histone tails. These histone marks are key to the processes of gene regulation. Deciphering the roles and mechanisms of the complexes that regulate chromatin is one of greatest challenges in understanding how genome activity is controlled. We aim to understand the roles and mechanism of action of a family of essential, non-redundant histone deacetylase complexes that control chromatin accessibility across the genome. These HDAC complexes share a common catalytic engine, but contain very different accessory proteins and have diverse oligomeric states. Although these are essential complexes, conserved from nematodes to man, we have only a very limited understanding of their mechanism of action. We will take two approaches to determine the mechanisms through which these complexes engage with their chromatin substrates and to understand how this determines their biological function. We will use structural techniques to determine the architectures of three exemplar complexes in complex with chromatin. We will use genomic and proteomic techniques to explore how these structures mediate their distinct biological activities.