Research

Genome-wide Analyses of Transcriptional Circuitry in Metabolic Signaling | Circadian Clocks and Energy Metabolism

Nutrients are processed for storage or the generation of ATP through chemical reactions that are collectively called energy metabolism. Mitochondrial oxidative phosphorylation (OXPHOS) provides the bulk of ATP that powers diverse biological processes and tissue functions. In mammals, the storage and oxidation of fuels are tightly controlled to maintain glucose and lipid homeostasis as well as overall energy balance. Disruption of this balance leads to metabolic syndrome, a global epidemic that is associated with increased risk for type 2 diabetes and coronary heart disease. The Lin lab is investigating mechanisms that regulate energy metabolism in response to nutritional and physiological signals and their role in the pathogenesis of metabolic diseases.

Genome-wide Analyses of Transcriptional Circuitry in Metabolic Signaling

Transcription factors regulate diverse biological processes by switching on and off gene expression. Although DNA-binding factors provide key information for selective target gene activation, our recent studies demonstrated that transcriptional coactivators are important, even dominant, regulators of complex biological programs. The PGC-1 family of coactivators, in particular PGC-1α and PGC-1β, responds to various nutritional and environmental signals and regulates mitochondrial biogenesis, lipid metabolism, and glucose homeostasis. These factors therefore serve as “hubs” that integrate biological signals and activate specific metabolic programs.

PGC-1 stimulates gene expression through interacting with transcription factors as well as cofactors involved in chromatin remodeling and histone modification. To gain insights into the molecular basis of metabolic regulation by the PGC-1 coactivators, we have developed a high-throughput coactivation assay that allows us to quantitatively measure the transcriptional activity of over 1,300 human transcription factors and cofactors. These studies reveal a global signature of the PGC-1 transcriptional network. We are currently investigating several novel factors in the control of mitochondrial OXPHOS, glucose and lipid metabolism.

Circadian Clocks and Energy Metabolism

Most living organisms exhibit behavioral and physiological rhythms that are regulated by the daily light-dark cycles. The temporal organization of metabolic functions is illustrated by the rhythmic expression of numerous genes involved in glucose and lipid metabolism as well as mitochondrial OXPHOS. In mammals, the central and peripheral clocks are controlled by a common regulatory circuitry composed of transcriptional activators and repressors that are assembled into feedback loops. It remains elusive, however, how mammalian clocks are integrated with diverse metabolic pathways and whether defects of normal metabolic rhythms contribute to the pathogenesis of insulin resistance and type 2 diabetes. We discovered that PGC-1α is rhythmically expressed in mouse tissues and it serves as a key link between the clock and metabolic pathways. PGC-1α regulates the expression of core clock genes through coactivating the ROR family of orphan nuclear receptors. We are currently investigating the role of molecular oscillations in metabolic control in normal and disease states.