Structural biology of signal transduction and epigenetic gene regulation
Figure 1: We employ a number of different resolution techniques to visualise the architecture of cellular components
Figure 2: Atomic model of the INF-β enhanceosome
The Panne group looks to understand important signalling processing pathways in the cell, which could help in the discovery of anti-viral drugs.
Previous and current research
Cellular control logic is ultimately embedded in the molecular architecture of the molecular machines that make up the living cell. Many molecular machines, especially complexes involved in cellular signalling, are transient, with a variety of states and a succession of structures. Transcription factors, for example, bind as complexes to enhancers (‘enhanceosomes’) in a combinatorial and dynamic fashion to regulate expression of genes. Kinases undergo major conformational rearrangements as part of their activation cycle. These signalling components interact with each other and with other molecules in highly structured but complex ways.
Understanding such transient and dynamic complexes of the cellular machinery is one of the most important challenges in biology today. One crucial first step towards characterising such dynamic processes is to determine the molecular architecture of essential components. We have been using the core approaches of structural biology to address the following questions: What is the architecture of signalling complexes that direct innate immune responses? How do these signalling pathways lead to assembly of higher-order transcription factor complexes? How does assembly of such transcription factor complexes ultimately lead to chromatin modification? How does chromatin modification direct nucleosome remodelling and gene regulation? (figure 1).
Future projects and goals
Cellular signalling ultimately results in assembly of transcriptional regulatory complexes that direct chromatin modification, remodelling and gene expression. The enhanceosome has served as a paradigm for understanding signal integration on higher eukaryotic enhancers (figure 2). Assembly of the enhanceosome results in recruitment of enzymes that modify chromatin. We ask how chromatin modification changes the structure of inhibitory nucleosomes and leads to a more permissive chromatin structure for gene expression. We also ask how chromatin modification enzymes read out histone modification patterns and how chromatin recognition and modification are coupled. Answers to some of these questions are likely to contribute to our understanding of epigenetic gene regulation and dysregulation in disease. Finally, we also are interested in understanding key regulators involved in the innate immune response. This is not only of fundamental importance for cellular signalling but also opens up opportunities for pharmacological targeting.