Date: Tuesday, 8 November 2016, 10 am (Manila Time)
Abstract
Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understands how this complex network regulates the metabolic response to fasting we aimed at isolating the enhancers and TFs dictating it. Measuring chromatin accessibility revealed that fasting massively reorganizes liver chromatin, exposing numerous fasting-induced enhancers. By utilizing computational methods in combination with dissecting enhancers features and TF cistromes, we implicated four key TFs regulating the fasting response: glucocorticoid receptor (GR), cAMP responsive element binding protein 1 (CREB1), peroxisome proliferator activated receptor alpha (PPARA) and CCAAT/enhancer binding protein beta (CEBPB). These TFs regulate fuel production by two distinctly-operating modules, each controlling a separate metabolic pathway. The gluconeogenic module operates through assisted loading whereby GR doubles the number of sites occupied by CREB1 as well as enhances CREB1 binding intensity and increases accessibility of CREB1 binding sites. Importantly, this GR-assisted CREB1 binding was enhancer-selective and did not affect all CREB1-bound enhancers. Single-molecule tracking revealed that GR increases the number and DNA residence time of a portion of chromatin-bound CREB1 molecules. These events collectively result in rapid synergistic gene expression and higher hepatic glucose production. Conversely, the ketogenic module operates via a GR-induced TF cascade whereby PPARA levels are increased following GR activation, facilitating gradual enhancer maturation next to PPARA target genes and delayed ketogenic gene expression. Our findings reveal a complex network of enhancers and TFs that dynamically cooperate to restore homeostasis upon fasting.
Ido Goldstein, PhD
Postdoctoral Fellow,
National Cancer Institute, USA
https://www.researchgate.net/profile/Ido_Goldstein
About the Speaker
Dr. Goldstein is a postdoctoral fellow at the US National Cancer Institute at the lab of Dr. Gordon Hager. His work is focused on transcriptional regulation in health and disease. During his graduate work, Dr. Goldstein discovered a link between the p53 transcription factor and lipid metabolism, drug detoxification and hepatic glucose production. While p53 was known to play a role in hepato-carcinogenesis, Dr. Goldstein’s work portrayed p53 also as a critical factor in hepatic homeostasis. Currently, Dr. Goldstein is using experimental and computational approaches to decipher the mode of cooperation between transcription factors at enhancer regions. A cooperation which eventually leads to synergistic gene expression. These cooperative transcriptional modules are essential for homeostasis and are perturbed in diseases such as diabetes, chronic inflammation and cancer.
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