Nutrient regulation of the islet epigenome controls adaptive insulin secretion
Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through...
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Published in | bioRxiv |
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Main Authors | , , , , , , , , , , , , , , , , |
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Cold Spring Harbor
Cold Spring Harbor Laboratory Press
21.08.2019
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Abstract | Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that β-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome. |
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AbstractList | Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that β-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome. |
Author | Sui, Yinghui Vinckier, Nicholas K Wallace, Martina Gaulton, Kyle J Wortham, Matthew Liu, Fenfen Chiou, Joshua Cross, Benjamin R Mulas, Francesca Huising, Mark O Shirihai, Orian S Sander, Maike Metallo, Christian M Patel, Nisha A Jhala, Ulupi S Fleischman, Johanna Y Harrington, Austin R |
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CitedBy_id | crossref_primary_10_3389_fgene_2020_590369 crossref_primary_10_3389_fendo_2022_842603 crossref_primary_10_1038_s41598_021_03567_3 crossref_primary_10_1038_s42255_021_00433_4 |
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SubjectTerms | Acetylation Adaptation Beta cells Blood glucose Chromatin Clonal deletion Diabetes mellitus Diabetes mellitus (non-insulin dependent) Gene regulation Genetic diversity Glucose Homeostasis Insulin Insulin secretion Secretion Transcription |
Title | Nutrient regulation of the islet epigenome controls adaptive insulin secretion |
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