Hormone regulation of transcription and characterisation of novel histone modifying enzymes

Dimitrios Cakouros, Alicia Paterson, Kathryn Mills, Zoe Kilpatrick, Donna Denton

The members of the nuclear hormone receptor (NHR) family bind their cognate ligands to regulate diverse physiological processes such as proliferation, differentiation and PCD by modulating transcription of a distinct array of genes. NHRs act via recruiting coactivators that are capable of modifying and remodelling chromatin structure. One of the projects in our lab is to understand the molecular mechanisms involved in hormone-mediated PCD by analysing the transcriptional regulation of the genes involved in apoptosis. We use both Drosophila and mammalian cells as experimental systems to study the function of NHRs in PCD. Ultimately all developmental signals lead to histone modifications such as methylation, acetylation, ubiquitination and phosphorylation, resulting in chromatin remodelling and gene activation and/or repression. In diseases such as cancer, enzymes that bring about these modifications are often deregulated.

We are identifying and cloning enzymes/proteins that regulate methylation/demethylation of histones in Drosophila and mammalian cells. With the recent discovery of the histone demethylase protein family, some of our current work involves the analysis of new histone demethylases involved in nuclear hormone mediated transcription, proliferation, differentiation and PCD in Drosophila. We are also studying potential roles of these epigenetic modifiers in cancer. We use cellular, molecular, proteomic and genetic approaches to study the functions of these enzymes.