Mechanisms of TLE3 Action in Adipose Subtype-selective Gene Expression

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DESCRIPTION (provided by applicant): Adipose tissue plays an important role in energy homeostasis by storing dietary energy in the form of triglyceride and releasing free fatty acids through hydrolysis of triglycerides in times of metabolic need. The study of adipocyte differentiation is becoming increasingly important given the role of adipose tissue in the pathogenesis of metabolic diseases such as obesity, insulin resistance, and cardiovascular diseases. Mammals have distinct specialized types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT stores energy whereas BAT is specialized to dissipate stored chemical energy in the form of heat and may have anti-obesity function. Recent studies have revealed an inherent plasticity of WAT to exhibit genetic and physiological features of BAT upon exposure to cold, ß-adrenergic agonists, or thiazolidinediones. The center of this phenotypic switch is peroxisome proliferator- activated receptor gamma (PPARγ), a master transcriptional regulator of both WAT and BAT differentiation. PPARγ is required for terminal adipocyte differentiation, as mice deficient for this nuclear receptor lack both WAT and BAT. The mechanism by which PPARγ directs adipose subtype-specific gene expression programs is still unclear. We recently discovered TLE3 as a dual-function WAT-specific PPARγ coregulator that forms both active and repressive transcriptional complexes to respectively drive WAT and suppress BAT differentiation. Moreover, our unpublished preliminary ChIP-Seq and RNA-Seq data show that i) genome-wide TLE3 binding correlates with both PPARγ enrichment on adipogenic regulatory sites and the regulation of adipose subtype-specific gene expression and ii) TLE3 binding is enriched in DNA regions containing several different pro-adipogenic transcription factor motifs. In this proposal we aim to determine the role of PPARγ:TLE3 axis in the nucleation of transcription factors and epigenetic modifications for WAT- and BAT-specific gene expression. We will also examine the consequence of TLE3 ablation on global adipocyte gene expression and PPARγ occupancy on gene promoter/enhancers. Overall, the concepts and methodologies used in this proposal will highlight the intricate balance between transcriptional programs and adipose-specific phenotype that may facilitate therapeutic manipulation of energy expenditure in patients with obesity and metabolic disorders.