Epigenetics in metabolic disease: stochastic, bi-stable and intergenerational effects

Abstract

Metabolic disease currently impacts beyond 1 billion people. Rates are rising with childhood obesity having than doubled in the last decade. This rapid rise in early life disease carries long-term health burden including heart disease, diabetes and stroke, making the issue one of the world’s chief economic and health care challenges of the day. While numerous studies have established a genetic framework for understanding metabolic disease, the contribution of critical regulatory layers, in particular epigenetic regulation, remain poorly understood. Our focus couples epigenomic analysis with functional genetics in mice to understand chromatin-coupled disease events and their direct implications for disease etiology. Recently, these efforts have uncovered novel roles for Polycomb silencing in buffering beta-cell dedifferentiation, as well as signalling modules that drive and potentiate beiging and browning of adipose tissues. They have also revealed mechanistic underpinnings for intergenerational control of non-genetic variation and what we believe to be the first stochastic disease ‘switch’ yielding distinct phenotypic ‘on’ and ‘off’ states in mouse and man. The data suggest the existence of polyphenism in mammals and have a profound influence on how we understand evolution and the genetic basis of phenotypic variation and disease.