Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response

Area of Science:

• Metabolic regulation
• Molecular biology
• Gene transcription

Background:

• Fasting induces significant metabolic shifts in hepatocytes, including glucose and ketone production.
• This metabolic reprogramming is orchestrated by complex transcriptional programs involving numerous transcription factors (TFs).
• Understanding the regulatory network of enhancers and TFs is crucial for deciphering the fasting response.

Purpose of the Study:

• To identify specific enhancers and TFs that govern the transcriptional response to fasting in hepatocytes.
• To elucidate the mechanisms by which these factors regulate glucose and ketone production during fasting.

Main Methods:

• Chromatin accessibility profiling to identify fasting-induced enhancers.
• Computational analysis of enhancer features and TF cistromes.
• Single-molecule tracking to study TF-DNA interactions.
• Analysis of gene expression changes related to glucose and ketone metabolism.

Main Results:

• Fasting reorganizes liver chromatin, revealing numerous fasting-induced enhancers.
• Four key TFs—glucocorticoid receptor (GR), CREB1, PPARA, and CEBPB—were implicated in regulating the fasting response.
• Two distinct modules were identified: a gluconeogenic module (GR-CREB1) and a ketogenic module (GR-induced PPARA cascade).
• GR enhances CREB1 binding and activity at specific enhancers, promoting rapid glucose production.
• GR activation leads to a PPARA cascade, facilitating gradual ketone production.

Conclusions:

• A complex network of enhancers and TFs dynamically regulates hepatic homeostasis during fasting.
• GR plays a dual role, synergizing with CREB1 for rapid glucose production and initiating a cascade for gradual ketone production.
• Enhancer-selective mechanisms and TF interactions are critical for fine-tuning metabolic fuel production.