ATACC · Polycomb and Trithorax Group Proteins: Master Regulators of Adipose Tissue Function?

Obesity and lipoatrophy are characterised by excess and paucity respectively of white adipose tissue. Both associated with insulin resistance, diabetes and cardiovascular disease, their prevalence will exceed 1 billion people by 2030. The convergence in metabolic phenotype of these two disparate disorders highlights how a precisely controlled, metabolically active adipose tissue is essential for proper health.Polycomb/Trithorax group (PcG/Trx) proteins were first identified in D. melanogaster as modulators of developmental patterning genes and are now recognized as fundamental executors of a chromatin-based silencing system that, capable of activating or silencing entire gene sets, is critical for multicellular development, differentiation and stem cell turnover. One of the most interesting features of PcG-induced gene-silencing patterns is to be transmitted through multiple cell divisions, thus touting them as mediators of cellular memory and critical to the stabilities of virtually all cell fates. Recent findings suggest a robust potential of PcG proteins to downregulate key developmental pathways involved in adipogenesis and adipose tissue function.Here we aim to define the role of PcG/Trx proteins in adipose tissue development, maintenance and function in vivo. This will be achieved by a multi-faceted approach including 1.functional characterization of temporally-inducible adipose tissue-specific PcG/Trx knock-out mice, 2.parallel profiling of gene expression, chromatin state, and PcG binding in mice and in highly characterized human samples from control and metabolically diseased patients, and 3.determination of mechanism through gain and loss-of-function approaches in vitro.Our plan merges the power of inducible gene targeting in mice with human genetics and disease biology. These approaches will help us understanding the role of chromatin remodeling in steady-state adipose tissue function and provide first hints at its contribution towards human disease.""