Functional Genomics for the identification of novel regulators of hepatic lipid metabolism: harnessing in vivo CRISPR/Cas9-based strategies (GENESIS)

Impaired hepatic lipid metabolism lies at the epicenter of many diseases our society is currently facing, including fatty liver and cardiovascular diseases. Therefore, it is essential to understand how hepatic lipid metabolism is regulated at the mechanistic level in health and disease, as this may lead to potential, eagerly needed and novel intervention strategies.

We and others have shown that whole-genome functional genetic screens in cell lines are a powerful tool to identify genes controlling biological processes, including lipid metabolism. A recognized pitfall of these in vitro screens is the identification of numerous potential “hits”, whose physiological relevance, if any, is unclear. To address this major limitation, in our project GENESIS we uniquely propose to circumvent this problem by setting up a unique whole-genome in vivo screen to identify potential positive and negative regulators of a central player in hepatic lipid metabolism in a physiological-relevant context.

Specifically, in this project, we will apply our distinctive screening, validation, and mechanistic characterization pipeline to discover physiologically-relevant regulators of SREBP1, a master regulator of lipid metabolism. SREBP1 is a transcription factor that integrates a wide range of metabolic and signaling cues and couples them to the regulation of genes involved in lipid metabolism. Beyond increasing our fundamental understanding how lipid metabolism is molecularly regulated in health and disease, our unique strategy offers a blueprint for other research fields to study biological processes in a physiologically relevant setting.