A chemical genetic approach to studying the role of epigenetics in development

This project will be part of a EU funded Marie Curie Initial Training Nework, the title of which is DevCom – Developmental and Computational Biology (http://mb01.azn.nl/devcom/).
The Neural Crest (NC) consists of multipotent cells that arise at the border between the ectoderm and the neural plate. They give rise to tissues such as craniofacial muscle, peripheral and enteric nerves and pigment cells. In adults NC derived tissues can give rise to neuroblastoma and melanoma. Recently we have shown that regulation of transcriptional elongation is important in NC development. From further work we have carried out we hypothesise that chromatin structure may also play a role in regulation of the NC. In this project we aim to identify small molecules that inhibit epigenetic regulation using NC development in Xenopus and zebrafish as model systems. We will test known inhibitors of epigenetic regulation as well as novel compounds. The perturbations in the gene regulatory networks will be analysed using RNA-seq and histone modification ChIP-seq. The experiments will shed more light on the epigenetic regulatory networks involved in neural crest development.
The project will identify small molecules that will be of use to investigators studying gene regulatory networks. In addition many of the proteins targetted by these molecules are increasingly being linked to particular diseases such as cancer, neurodevelopmental disorders, cardiovascular diseases, type-2 diabetes, obesity and infertility as well as with ageing. Inhibitors that are shown to work in the whole organism will therefore be potentially of use in drug discovery.

The project will combine training in developmental biology techniques, biochemistry, bioinformatics and chemoinformatics. Workshops with other students in the Training Network will occur throughout the PhD.