The molecular functioning of HDAC:co-repressor complexes

Histone deacetylases (HDACs) are essential enzymes required for human development and homeostasis and they are increasingly recognised as important targets for the treatment of cancer and other diseases, including Alzheimer's. HDACs 1-3 serve as catalytic subunits in several large transcriptional co-repressor complexes that are recruited to chromatin by repressive transcription factors. These complexes remove acetyl groups from histones, resulting in the condensation of chromatin, which causes gene silencing. Professor Schwabe plans to determine the structures of the four HDAC1 and HDAC3 holo-complexes, in order to define the specificity of their assembly and their role in determining target gene and substrate specificity. He will also be researching the biological role of inositol tetraphosphate in regulating HDAC complexes and the potential therapeutic targeting of HDAC:co-repressor complexes by both small molecules and interfering peptides.