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Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response
Open accessAbstract
Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understand 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 enhancer 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.
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“Assisted loading has been described in various systems30–37.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [37]
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Metadata
- Authors
- Goldstein, I., Baek, S., Presman, D. M., Paakinaho, V., Swinstead, E. E., & Hager, G. L.
- Affiliations
- National Institutes of Health (US)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2016-12-28
- Volume
- 27
- Issue
- 3
- Pages
- 427-439
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC5340970
- OpenAlex
- W2566710076
- Cited by
- 121
- References
- 51
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 17 · 2023: 16 · 2022: 15 · 2021: 13 · 2020: 14 · 2019: 11 · 2018: 6 · 2017: 9
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genome Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- HighWire Press Open Archive (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- National Cancer Institute
- Center for Cancer Research
- Sigrid Jusélius Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- fasting response, hepatic glucose production, ketogenesis, transcription factors, enhancer dynamics, chromatin accessibility, glucocorticoid receptor, CREB1, PPARα, CEBPB, single-molecule tracking, hepatic metabolism
- MeSH terms
- Animals, Binding Sites, Chromatin, Enhancer Elements, Genetic, Fasting, Glucose, Ketones, Male, Mice, Inbred C57BL, Receptors, Glucocorticoid, Transcriptional Activation, Cyclic AMP Response Element-Binding Protein, Hepatocytes, CCAAT-Enhancer-Binding Protein-beta, Chromatin Assembly and Disassembly, PPAR alpha, Mice
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