학술논문
Nutrient regulation of the islet epigenome controls adaptive insulin secretion
Document Type
article
Author
Wortham, Matthew; Liu, Fenfen; Harrington, Austin R; Fleischman, Johanna Y; Wallace, Martina; Mulas, Francesca; Mallick, Medhavi; Vinckier, Nicholas K; Cross, Benjamin R; Chiou, Joshua; Patel, Nisha A; Sui, Yinghui; McGrail, Carolyn; Jun, Yesl; Wang, Gaowei; Jhala, Ulupi S; Schüle, Roland; Shirihai, Orian S; Huising, Mark O; Gaulton, Kyle J; Metallo, Christian M; Sander, Maike
Source
Journal of Clinical Investigation. 133(8)
Subject
Language
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.