The Panne group looks to understand how signalling pathways control gene expression, focussing on signalling in the innate immune system, epigenetic control of gene expression and chromatin assembly.
Previous and current research
Our research has focused on understanding how signalling pathways control gene expression by regulating chromatin assembly. We are particularly interested in pathways of the innate immune system that regulate gene expression. Pattern recognition receptors such as RIG-I or STING couple to IKK kinases such as TBK1 that regulate NFkB and IRF3/IRF7 activation. Once these transcription factors are activated, together with ATF2/c-Jun they form a higher-order regulatory structure called the ‘enhanceosome’ that regulates gene expression of interferon (figure 1). Higher-order transcription factor complexes such as the enhanceosome frequently recruit the co-activators CBP/p300. CBP/p300 are important to integrate the cellular signals by providing a scaffold function. CBP/p300 also modify chromatin and ultimately, in conjunction with remodellers and histone chaperones, makes chromatin permissive for gene transcription.
Understanding information transfer by such transient and dynamic complexes of 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 concerning information transfer in this system: What is the architecture of signalling complexes that direct innate immune responses and control gene expression? 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? How does cohesin contribute to the regulation of chromatin architecture?
Future projects and goals
Cellular signalling ultimately results in the 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 1). 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 cohesin, a topological ring complex that entraps sister chromatids, contributes to chromatin regulation. Answers to some of these questions are likely to contribute to our understanding of chromatin regulation and dysregulation in disease. This is not only of fundamental importance for cellular signalling, but also opens up opportunities for pharmacological targeting.