The Panne group looks to understand important signalling processing pathways in the cell, which could help in the discovery of anti-viral drugs.
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.
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. For example, transcription factors such as NFkB, IRF3, IRF7 and ATF2/c–Jun bind as complexes to enhancers (‘enhanceosomes’) in a combinatorial and dynamic fashion to regulate expression of genes (figure 1). Enhanceosome assembly is mediated by a set of IKK kinases such as TBK1 that regulate NFkB and IRF3/IRF7 activation. 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 important first step toward characterising such dynamic processes is to determine the molecular architecture of essential components. We are using a combination of biophysical techniques including X-ray crystallography, electron microscopy, native mass spectrometry, and more 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 regulatory complexes? How does assembly of such transcription factor complexes ultimately lead to chromatin modification? How does chromatin modification direct nucleosome remodelling and gene regulation?
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 such as CBP/p300 that acetylate chromatin. We aim to understand how recruitment of CBP/p300 allows cellular signal integration and chromatin acetylation. We ask how chromatin acetylation changes the structure of inhibitory nucleosomes and leads to a more permissive chromatin structure for gene expression. We also ask how CBP/p300 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. This is not only of fundamental importance for cellular signalling, but also opens up opportunities for pharmacological targeting.