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Polycomb/Trithorax: Functional EpiGenomics Integrators for Metabolic Disease

Final Report Summary - METABOLICPOLYCOMBICS (Polycomb/Trithorax: Functional EpiGenomics Integrators for Metabolic Disease)

The current project aimed to intersect two disciplines, namely metabolic disease biology and epigenetic control. There were three major aims: First, generate novel conditional mutant mice as a platform for some of these investigations and as new resources for the field. Second, use these tools to gain an understanding of PCG function in control metabolic tissues, their development and their function. And third, push and take advantage of state-of-the-art technologies to generate the first epigenetic maps of mouse and human obesity. The goal for all three aims are to develop a deeper understanding of how epigenetic control systems guide phenotype, how they guide phenotypic variation, and how they influence disease susceptibility or even drive disease.
For our first two aims, we generated at least 6 novel conditional deletion mutations including deletions of core structural and enzymatic components of PcG complexes. These mutants have focused on understanding PcG function in pancreatic beta-cells and liver. Through the latter approach, in particular, we find surprising new regulatory circuits for metabolic set-points and interestingly, control of inter-organ communication. More specifically, examining PcG function in beta-cells, we find that deletion of the enzymatic components versus structural components are not equal. Whereas elimination of the core enzymatic unit gives a relatively mild overall phenotype showing loss of a simple loss of beta-cell proliferative potential, deletion of the core structural center of the complex results in an amazing highly synchronous and fully penetrant de-differentiation phenotype. These data already allow us to make several powerful conclusions: At least in the context of the beta-cell, PcG control of transcriptional programs goes well beyond it’s H3K27 methylase acivity. Indeed, alternate roles appear of even greater importance with respect to controlling the stability of cell identity and transcriptional programs. The data provide potential insights into beta-cell aging. Intriguingly, beta-cell de-differentiation was recently suggested to be a hallmark of the type-2 diabetic islet. Our models now give us a deep and precise functional window into the processes potentially underlying this human disease etiology. Notably, while probing the opposing biological pathways, we have preliminary evidence that this process is preventable and thus potentially amenable to therapeutic targeting. The latter though is indeed providing intriguing new insights into adipose tissue biology. Beta-cells aside, our investigations in the liver indicate that PcG complexes specifically several gene signatures but in particular, several key adipose regulating hepatokines. These models appear highly protected from high fat diet induced metabolic disease, at least in part, through a browning of select brown adipose tissue depots.
Perhaps most important the project has changed our understanding on epigenetics of disease. We identified polyphenism in mammals, a concept that states that each one of us could have come out a different, second person; much like a queen bee versus a worker bee. This concept appears to be true in humans to and could radically change how we view complex disease susceptibility and therapeutic response. It adds an entire new dimension to the concept of personalized medicine. Finally, interacting in the contexts of several key networks we have generated major resources for unbiased discovery of new disease causing genes and mutation by epigenomic mapping of disease. Partner consortium include DEEP (the German Epigenome Project), MEDEP (a regional network on medical epigenetics), and Epigenesys (an EU network of excellence focusing on systems biology and epigenetics). Together our vision of mapping the epigenomic state changes that correlate and even drive obesity have become reality. We’ve thus set in motion a new wave of research to deepen our understanding of epigenetic control of obesity and type-2 diabetes.