The evolutionarily conserved Hippo pathway plays an important role in organ size control by maintaining a precise balance of cell proliferation and cell death, and deregulation of Hippo signalling is observed in many cancer types. In Drosophila melanogaster, the downstream regulator of the pathway is the transcriptional coactivator protein Yorkie (Yki). Overactivity of Yki leads to hyperproliferation and overgrown tissues as a result of deregulation of target genes. Yki interacts with a number of transcription factors, for example Scalloped (Sd), to regulate the expression of genes. A repressor protein called Tondu-domain-containing growth inhibitor (Tgi) competes with Yki for Sd binding and the Sd-Tgi interaction results in repression of target genes. In this way, Yki promotes growth by relieving Sd and Tgi-mediated gene repression.
My phD research involves identifying the target genes regulated by the Hippo pathway in different growth contexts. Employing a powerful technique called targeted DamID, my research aims to identify and compare the target genes of Yki, Sd, and Tgi in wild type and hyperplastic tissue growth. Furthermore, in order to elucidate if Yki and Tgi require Sd for regulating their respective target genes, I will investigate Yki and Tgi target genes in a Sd mutant.
My studies have found that Yki, Sd, and Tgi bind to hundreds of genes in proliferating cells, including genes involved in signalling pathways such as MAPK signalling, Wnt signaling and the TGF-β pathway. Interestingly, many of these target genes are shared between Yki, Sd, and Tgi, indicating that they cooperate to control tissue growth by regulating the activity of many target genes and balancing target gene activation and repression.
Identifying the transcriptional targets of Hippo signalling will greatly expand our knowledge and understanding of how the Hippo pathway functions to control growth and how its deregulation can result in tumourogenesis.