Why should we consider epigenetics in metabolic disorders?
Complex metabolic disorders including obesity and type 2 diabetes result from intricate interactions between internal genetic makeup and external environment, which is mediated by epigenetic mechanisms. There are compelling reasons to think epigenetic control may have a direct role in the pathogenesis of metabolic dysregulation; 1) Genetic differences can not fully explain many etiological features of metabolic disorders, such as high heritability, high discordance of metabolic disorders in adult monozygotic twins, and the close relationship with lifestyle factors. Therefore, other forms of non-genetic variation, such as epigenetic alterations, should be considered in the etiology. 2) Drugs that affect chromatin remodeling, such as the HDAC inhibitors are known to affect insulin sensitivity in cells, animal models, and human subjects. 3) Collective studies report global and locus-specific epigenetic changes at key metabolic genes often accompanying reduced gene expression in association with various metabolic perturbations. 4) Most convincingly, studies have shown that several mouse genetic models carrying mutations in genes encoding epigenetic modifiers display marked metabolic phenotypes. Despite these notions, the accurate role for the epigenetic modifiers in metabolic regulation largely remains unknown.
Epigenomic profiling is a powerful discovery tool.
Insulin resistance is a sine qua non of type 2 diabetes and is associated with many other clinical conditions including obesity, cardiovascular diseases, and cancer. As an effort to identify novel transcriptional pathways of insulin resistance, we constructed global transcriptional and H3K27ac enhancer maps of insulin resistance using comparative models of insulin resistance induced by dexamethasone (Dex) or tumor necrosis factor- (TNF) in cultured adipocytes. As a result, we detected several locus-specific H3K27ac positive enhancers that display coordinate regulation nearby the co-induced genes by Dex and TNF. Motif analysis on these enhancer regions led us to discover transcriptional pathways insulin resistance, from which I demonstrated the biological significance of the glucocorticoid receptor (GR) and vitamin D receptor (VDR) as common nodes for Dex and TNF mediated insulin resistance. Further, through integrative analysis of our epigenomic and transcriptomic data, we unraveled a core target genes of GR and VDR that can be used as molecular signature of insulin resistance. These studies illustrate the power of epigenomic profiling as a tool for the identification of novel pathogenic disease mechanisms.
Our research mission
Our research goal is to gain more accurate understanding of how epigenetic and transcriptional regulators control (patho)physiology of adipose and other metabolic tissues. Ultimately, we hope to identify novel drug targets for more safe and efficient therapeutic intervention to relevant metabolic disorders including obesity and type 2 diabetes. The key questions that we address are; 1) What are the core epigenetic events underlying obesity and insulin resistance, especially in the fat tissue? 2) Does the adverse epigenetic have a direct contribution to the pathogenesis?, 3) If so, how does so?, and, 4) Can we fix the adverse epigenetic events to mitigate the condition?
To answer these questions, we are uniquely geared to integrate a wide variety of approaches, from highly mechanistic studies in vitro and in vivo, metabolic characterization of genetically modified mouse models, and to global profiling studies such ahs ChIP-Seq and RNA-Seq.