Discovering how CpG islands control transcription to regulate gene expression
Year of award: 2024
Grantholders
Prof Martin Howard
John Innes Centre, United Kingdom
Prof Robert Klose
University of Oxford, United Kingdom
Project summary
The remarkable process of multicellular development requires that cells initiate and then maintain highly-defined gene expression programs. We have recently discovered that CpG island (CGI) elements guide the formation of distinct chromatin-states at gene promoters and these play a fundamental role in specifying appropriate gene expression. Despite these advances, how CGI-guided chromatin-states control transcription to regulate gene expression remains enigmatic and is a central outstanding question in our most basic understanding of gene regulation. Here we will use a bold, multidisciplinary, and collaborative approach to discover how CGI-defined chromatin-states control transcription to repress (Aim1) or enable (Aim2) gene expression, and use this new mechanistic insight to test our hypothesis that CGIs integrate chromatin-based activities to create decisive switch-like transitions in gene expression during cell lineage commitment (Aim3). In addressing these important questions, our new discoveries will enable us to develop a quantitative and predictive model for CGI-dependent gene regulation and in doing so redefine our understanding of how gene promoters function to control gene expression in normal and disease biology.