Dr Christopher Douse (Dept of Medicine) has been awarded a BBSRC Future Leader Fellowship to continue research to understand the structure and gene silencing mechanism of TASOR, part of the newly discovered Human Silencing Hub (HUSH). Working with Dr Yorgo Modis and in collaboration with Professor Paul Lehner’s laboratory, he will be examining molecular details of the HUSH complex, which is involved in gene silencing at sites of retroviral integration. This will not only improve our understanding of this novel biological mechanism, but also provide a template for establishing the druggability of the complex.
Heterochromatin, the regions in the nucleus in which genomic DNA is more tightly packaged, is associated with repression of gene transcription. This transcriptional silencing is regulated by an epigenetic code of histone modifications, for example tri-methylation of lysine 9 on histone 3 (H3K9me3). The positioning of a gene in heterochromatin may result in different rates of transcription depending on the heterochromatic environment of the gene, and its resulting epigenetic marks: this effect is known as position-effect variegation (PEV). By using forward genetic screens, analogous to those used in Drosophila melanogaster to search for genes involved in PEV, in human cells, Lehner and co-workers recently identified a novel transcriptional silencing complex: the Human Silencing Hub (HUSH) . This complex is conserved from fish to humans and is responsible for silencing newly integrated retroviral genes, as well as cellular genes, through recruitment of the SETDB1 H3K9 methyltransferase. Details of the assembly, mechanism and regulation of this multi-protein complex are not understood at the molecular level. In particular, the 1670-amino acid, hitherto-uncharacterized protein transgene activation suppressor (TASOR) is required for HUSH gene silencing activity and appears to organize the HUSH complex . The aim of this project is to identify and isolate the functionally important domains of TASOR, and to elucidate their structure and function. The project will combine complementary cell biological approaches with high-resolution structural and biophysical approaches to build a mechanistic model of how the HUSH complex establishes and maintains its gene silencing activity.