Structural biology of transcriptional repression complexes
The major focus of my research group is to understand the molecular mechanisms that underlie the epigenetic reprogramming of the genome during cellular differentiation and development. Our particular interest is in Histone Deacetylase (HDAC) complexes whose primary role is to remove acetyl groups from lysine sidechains within the tails of histone proteins. This results in hypo-acetylated chromatin, which is the first step in gene inactivation.
The Class 1 HDACs form the catalytic core of six families of HDAC-containing complexes that are targeted to chromatin. These contain the class I HDACs 1, 2 or 3 along with a variety of other proteins that target the complex to chromatin and/or possess other enzymatic activities. Importantly, the enzymatic activity of the HDACs requires assembly into these complexes.
These complexes are promising drug targets for the treatment of multiple disorders including cancer, Alzheimer’s Disease and HIV. To date at least six drugs which target HDACs are licensed for use in humans to treat certain types of cancer. Currently these drugs lack true isoform and complex specificity and therefore have adverse side-effects. By understanding the assembly and architecture of these complexes we hope to be able to develop drugs that are specific for single complexes.
We take an integrated structural biology approach to seek to understand this diverse family of HDAC complexes. We have recently made several major advances using X-ray crystallography techniques and we are now combining these studies with techniques such as negative-stain and cryo-electron microscopy, small-angle X-ray scattering and cross-linking mass spectrometry. These approaches can overcome the limitations of X-ray crystallography in studying large and somewhat flexible complexes. Using the information from structural biology we then utilise a wide variety of complementary techniques from biophysical to cell biology assays to fully understand their structure and function. We collaborate with groups from within the Institute and Department of Molecular and Cell Biology to develop chemical tools and probes (James Hodgkinson), to understand the function of these complexes in cells and animal models (Shaun Cowley / Andrew Fry).
- Kalin JH, et al (2018) Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nat Commun. 9(1):53
- Millard CJ, et al. (2016) 'The structure of the core NuRD repression complex provides insights into its interaction with chromatin.' eLIFE, vol. 5. P. e13941.
- Watson PJ, et al. (2016) 'Insights into the activation mechanism of class I HDAC complexes by inositol phosphates.' Nat Commun, vol. 7. P. 11262.
- Millard CJ, et al (2013) 'Class I HDACs share a common mechanism of regulation by inositol phosphates.' Mol Cell. 11;51(1):57-67.
- Watson PJ, et al. (2012) 'Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.' Nature, vol. 481. Pp. 335–340.
Louise Fairall, Chris Millard, Robert Turnbull, Yun Song, Vasileios Paschalis, Beatriz Romartinez, Chia-Liang Lin, Liam Regan, Jennifer Gurnett, Almutasem Saleh, Siyu Wang, Edward Brown, Oksana Gonchar.