Genome binding/occupancy profiling by high throughput sequencing
Summary
During fasting transcriptional programs lead to glucose and ketone production. The major TFs, their crosstalk and the enhancers driving it are unknown. We show that fasting massively reorganizes liver chromatin to expose 'fasting enhancers'. By tracking TF footprints, we implicated the major TFs regulating fuel production by two modules. The ketogenic module is executed by a temporally-organized TF cascade. Conversely, in the gluconeogenic module glucocorticoid receptor (GR) augments cAMP-response element-binding protein (CREB) activity in an enhancer-selective manner. Using genomics and single-molecule tracking, we show that GR enhances the number of bound CREB molecules and the quantity, intensity and accessibility of CREB binding sites; leading to synergistic gene expression and glucose production. Our findings reveal that TFs dynamically and cooperatively respond to environmental signals to restore homeostasis.
Overall design
characterization of liver transcription factor binding and histone acetylation during fasting using chromatin immunoprecipitation
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