Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function
Objective: Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components and act through β-cell-specific enhancers. However, their relationship is unclear. Methods: In this report,...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821001010 |
| _version_ | 1818741877576302592 |
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| author | Taiyi Kuo Wen Du Yasutaka Miyachi Prasanna K. Dadi David A. Jacobson Daniel Segrè Domenico Accili |
| author_facet | Taiyi Kuo Wen Du Yasutaka Miyachi Prasanna K. Dadi David A. Jacobson Daniel Segrè Domenico Accili |
| author_sort | Taiyi Kuo |
| collection | DOAJ |
| description | Objective: Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components and act through β-cell-specific enhancers. However, their relationship is unclear. Methods: In this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells enriches active Hnf4α enhancers according to a HOMER analysis. Results: To model the functional significance of this predicted unusual enhancer utilization, we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea and calcium fluxes. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues was completely reversed in double mutants lacking FoxO1 and Hnf4α. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of β-cell dysfunction. An antagonistic network regulating glycolysis, including β-cell “disallowed” genes, and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. Conclusions: The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction. |
| first_indexed | 2024-12-18T02:03:36Z |
| format | Article |
| id | doaj.art-4238f9e1168c468b80aa8a3a188fa866 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-18T02:03:36Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-4238f9e1168c468b80aa8a3a188fa8662022-12-21T21:24:40ZengElsevierMolecular Metabolism2212-87782021-11-0153101256Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell functionTaiyi Kuo0Wen Du1Yasutaka Miyachi2Prasanna K. Dadi3David A. Jacobson4Daniel Segrè5Domenico Accili6Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA; Corresponding author. Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, 1150 St. Nicholas Avenue, Room 237, New York, NY, 10032, USA.Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USADepartment of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USADepartment of Biology, Department of Biomedical Engineering, Department of Physics, Boston University, Boston, MA, USADepartment of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USAObjective: Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components and act through β-cell-specific enhancers. However, their relationship is unclear. Methods: In this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells enriches active Hnf4α enhancers according to a HOMER analysis. Results: To model the functional significance of this predicted unusual enhancer utilization, we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea and calcium fluxes. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues was completely reversed in double mutants lacking FoxO1 and Hnf4α. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of β-cell dysfunction. An antagonistic network regulating glycolysis, including β-cell “disallowed” genes, and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. Conclusions: The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.http://www.sciencedirect.com/science/article/pii/S2212877821001010Beta cellHnf4aFoxo1EnhancerInsulinEpistasis |
| spellingShingle | Taiyi Kuo Wen Du Yasutaka Miyachi Prasanna K. Dadi David A. Jacobson Daniel Segrè Domenico Accili Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function Molecular Metabolism Beta cell Hnf4a Foxo1 Enhancer Insulin Epistasis |
| title | Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function |
| title_full | Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function |
| title_fullStr | Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function |
| title_full_unstemmed | Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function |
| title_short | Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function |
| title_sort | antagonistic epistasis of hnf4α and foxo1 metabolic networks through enhancer interactions in β cell function |
| topic | Beta cell Hnf4a Foxo1 Enhancer Insulin Epistasis |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821001010 |
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