Discovering how CpG islands control transcription to regulate gene expression

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.