Understanding the mechanistic relationship between 3D gene structure and transcription

A role for 3D gene structure in regulating transcription has been hypothesised, but direct evidence remains limited. This restricts our understanding of the mechanisms through which chromatin misfolding leads to disease. To understand the relationship between structure and transcription in human cells we will integrate molecular biology approaches and cutting-edge mechanistic polymer models of chromatin. Such models are well-suited to explore parameter space, predict molecular properties, and generate hypotheses to provide a framework for laboratory experiments. Using minimal bioinformatic data, a new polymer model to predict gene structure and transcriptional activity in healthy or diseased cells will be developed and experimentally validated. We will then assemble the first genome-wide, 3D gene structure compendium and use it as a foundation to determine if structure has evolved to regulate transcription. Polymer models predict a range of possible structures. We will combine simulations and experiments to test whether such intra-gene structural heterogeneity regulates transcriptional noise and will identify the mechanisms involved through locus engineering. Finally, as the protein SAF-A interacts with RNA to regulate gene architecture, we will incorporate RNA fields into simulations and experimentally investigate the concept that protein/RNA gels can impact transcription, thereby characterising a novel feedback between structure and function.