The last decade has seen an explosion of research into the epigenetic regulation of cell biology. Indeed, great efforts have been made to elucidate epigenetic regulation in stem cell biology, development, and within the plastic states of cancer. Current estimates place the prevalence of obesity in the range of 300 million to beyond 1 billion by the year 2030. As a critical risk factor for heart disease, diabetes and stroke, obesity currently represents one of the world’s chief economic and health care challenges. While studies have established a genetic framework for our current understanding of obesity, the contribution of several critical regulatory layers, in particular epigenetic regulation, remains poorly understood.We recently performed the first genome-wide RNAi screen for obesity regulators in the adult fly. Intriguingly, developmental regulators scored among the most enriched pathways (Pospisilik, Cell 2010). Systematic interrogation of the 500 candidate obesity genes by tissue-specific knockdown has now identified the Polycomb-Trithorax system (PcG-Trx) as the most enriched obesity-altering pathway. Here, we propose to translate these findings to the mammalian context through completion of three aims: i. generation and characterization of 8 PcG conditional knockout mouse lines, ii. dissection of the functional roles of PcG in adipose tissue differentiation, function and disease, and iii. building of a functionally interrogated unbiased epigenetic map of the PcG-system for murine and human obesity. To achieve these goals we will combine targeted mouse genetics, complex phenotyping and state-of-the-art integrative bioinformatics.Using this unique functional-genetics-to-epigenomics approach we will provide an unprecedented functionally validated genomics resource for obesity research worldwide, unravel an entire regulatory niveau in obesity, and if we are lucky, highlight novel therapeutic strategies for metabolic disease.