Understanding the mechanistic relationship between 3D gene structure and transcription

Understanding the three-dimensional structure of genes is important, it is linked to gene activity, but the mechanisms are unclear. To unravel them, we will integrate genome-wide computer simulations with high-resolution laboratory experiments in human cells. As a foundation we have developed a polymer model to predict the 3D structures and transcriptional activity of genes. This provides a framework to direct laboratory experiments to quantify and characterize topological interactions and underlying mechanisms. We will start by mapping the 3D structure of all human genes and then ask if 3D gene structures have evolved to regulate transcription, and if different gene structures affect transcriptional heterogeneity. Finally, we will model how protein/RNA gels impact gene structure and transcription and dissect the molecular details by mutating the key proteins involved. Our study will transform how we understand the relationship between gene structure and transcription, and the consequences of chromatin protein mutations that cause disease.