Protein SUMOylation and transcriptional control in a dynamic 3D chromatin environment

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The decoding of our genome through the process of gene transcription ultimately dictates the form and activity of the cells in our body. Importantly, this decoding activity is not static but is dynamic and changes in response to intra and extracellular cues. These dynamic responses are controlled by pathways such as the ERK signalling cascade which ultimately impact on gene expression profiles. This pathway is important for normal cellular responses in our immune systems and brains, which enables us to function normally in combatting microbial infections and process information. Once deregulated, this pathway can lead to disease states, as exemplified by its frequent hyperactivation in cancer. Our preliminary work has shown that the target genes for this pathway exist in complex 3-dimensional environments, whereby multiple control elements cluster together. Furthermore, we demonstrate that these control elements are marked by a protein called SUMO and that this modification is dynamically deposited across genes as transcription proceeds. This is suggestive of an important role for SUMO. In this project we will examine the role of SUMO in inducible gene regulation. First we will assess the role of SUMO in creating a local 3D structure that facilitates gene expression. Next we will ask how SUMO effects gene activation and determine relevant target proteins that are involved in this process. This will enable us to understand how the switches that control gene transcription are regulated. This is important, not only in the context of ERK pathway signalling but more broadly as SUMO has been shown to play a critical role in cell fate decisions, which is of particular relevance in iPS cell generation which are the building blocks used in regenerative medicine.