Transcription cycle regulation by nutrients

项目总结

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated global prevalence of 1 in 4 individuals. No FDA-approved treatments are available. Aberrant transcriptional control of gene expression is central to the pathophysiology of metabolic diseases. Transcription by RNA Polymerase II (RNAP2) occurs through several coordinated steps, which include pre-initiation complex formation and initiation, elongation, and termination. The assembly of the basal transcription machinery and transcription initiation was believed for many years to be the rate-limiting and most important aspect driving gene expression. Recent research has revealed that the transition from initiation to elongation is a rate-limiting and critical step, requiring specific signals to release RNAP2 from its paused state and engage in transcription elongation. RNAP2 pause-release is a mechanism that allows fast and synchronized gene expression in response to environmental cues, adjusting expression of entire gene programs. The process of pause-release requires histone H3 acetylation at lys9 (H3K9ac) in the promoter-proximal region. H3K9ac levels are significantly altered by high-fat feeding in mice, a model of diet-induced obesity, insulin resistance and NAFLD. We hypothesize that RNAP2 pause-release is a fundamental mechanism of gene regulation in response to nutrient availability, and under conditions of nutrient excess, misregulated pause-release contributes to aberrant changes in gene expression. To study how cells respond to nutrients at the genome-wide level, high- throughput sequencing technologies will be used. The goals of this proposal will be achieved by pursuing the following specific aims: (i) Define the role of RNAP2 pause-release in transcription regulation in the fasted to refed transition; (ii) Determine the mechanism by which the pro-lipogenesis transcription factor Sterol Regulatory Element Binding Protein 1 (SREBP-1) contributes to regulate transcription elongation; (iii) Determine how H3K9ac contributes to change gene expression under high-fat conditions. This proposal is significant because it will identify a novel node of transcription regulation, breaking new ground for drug target discovery. Thus, this proposal addresses a basic scientific gap in the field of metabolism, and the results of these innovative studies could lead to the development of new and effective therapeutic interventions for NAFLD, type 2 diabetes and other associated metabolic diseases.