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Nutrient regulation of the islet epigenome controls adaptive insulin secretion

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Item Type:Article
Title:Nutrient regulation of the islet epigenome controls adaptive insulin secretion
Creators Name:Wortham, M. and Liu, F. and Harrington, A.R. and Fleischman, J.Y. and Wallace, M. and Mulas, F. and Mallick, M. and Vinckier, N.K. and Cross, B.R. and Chiou, J. and Patel, N.A. and Sui, Y. and McGrail, C. and Jun, Y. and Wang, G. and Jhala, U.S. and Schüle, R. and Shirihai, O.S. and Huising, M.O. and Gaulton, K.J. and Metallo, C.M. and Sander, M.
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 have shown 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 occurred at sites occupied by the chromatin-modifying enzyme Lysine-specific demethylase 1 (Lsd1) in islets. β-cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.
Keywords:Epigenome, Glucose, Histones, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Type 2 Diabetes Mellitus, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:e165208
Date:17 April 2023
Official Publication:https://doi.org/10.1172/JCI165208
PubMed:View item in PubMed

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