Probing transcriptional activation at the molecular level

Project summary Our work has focused on answering two fundamental and long-standing questions in transcription initiation: what are the underlying molecular recognition principles governing transcriptional activator (TA)-coactivator complexes and, relatedly, are the complexes druggable. The importance of these questions is apparent considering the central role TA-coactivator complexes play in steering the assembly of the transcription machinery at gene promotors. Early in transcription, coactivators are recruited to genomic loci by DNA-bound TAs and it is the transient and structurally dynamic TA-coactivator PPI network that promotes essential epigenetic alterations and primes RNA polymerase for transcription initiation. Conversely, dysregulation of TA-coactivator PPIs is implicated in numerous pathologies and for that reason TA-coactivator PPIs are high- value targets for probe molecules and therapeutics. Here we will harness the molecular recognition principles and synthetic modulator discovery strategies developed in the previous funding period to re-wire transcriptional circuits that are dysregulated in cancer and intellectual disability. In doing so we will provide a set of synthetic inhibitors and enhancers of TA-coactivator complexes available to the broader community and define druggable nodes for therapeutic development.