Every human cell relies on a set of enzymes called histone deacetylases (HDACs) to switch genes off by tightening the packaging of DNA. These enzymes are already targets for cancer drugs, but exactly how they assemble into larger protein complexes and choose which genes to silence remains poorly understood. This project will determine the three-dimensional structures of four key HDAC complexes, revealing the molecular rules that govern their assembly and their ability to recognise specific genes. The researchers recently discovered that a small signalling molecule, inositol tetraphosphate (IP4), acts as an essential regulator of one such complex—a finding that suggests an entirely new mechanism for controlling gene repression. By mapping these structures and testing how IP4 controls the complexes, the work will explain fundamental processes in human development and tissue maintenance. In the longer term, understanding these molecular details could guide the design of more selective drugs that target specific HDAC complexes, potentially reducing side effects in cancer treatment and opening avenues for diseases like Alzheimer’s where gene regulation goes awry.
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Histone deacetylases (HDACs) are increasingly recognised as important targets for the treatment of cancer and other diseases including Alzheimer's. They are essential enzymes required for human development & homeostasis. HDACs 1-3 serve as the catalytic subunits in several large transcriptional co-repressor complexes that are recruited to chromatin by repressive transcription factors. These complexes function by removing acetyl groups from histones resulting in condensation of chromatin and gen e silencing. Our research is concerned with elucidating the fundamental mechanisms through which HDACs 1-3 are regulated and how they target chromatin. Our recent structure of the HDAC3 co-repressor complex identified the small signalling molecule inositol tetraphosphate (IP4) as an essential co-factor (Nature 2012, 481, 335). The breakthrough realisation that IP4 acts as an epigenetic regulator suggests a completely new and unexpected mechanism for the regulation of gene repression. More rece ntly still, we have determined the structure of HDAC1 bound to the Metastases Associated Protein co-repressor (unpublished). This structure not only reveals the basis for the specific assembly of HDACs into their cognate complexes, but also reveals how the complex is targeted to chromatin. We propose to address the major outstanding questions concerning the biological role and mechanisms of action of histone deacetylase complexes: (i) to determine the structures of the four HDAC1 and HDAC3 hol o-complexes, defining the specificity of assembly and their role in determining target gene and substrate specificity (ii) to understand the biological role of IP4 in regulating HDAC complexes (iii) to explore potential therapeutic targeting of HDAC:co-repressor complexes by both small molecules and interfering peptides
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