Nutrient regulation of the islet epigenome controls adaptive insulin secretion

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. MainThe ability to regulate nutrient metabolism in response to feeding and fasting is necessary for metabolic homeostasis. Nutrient utilization is acutely regulated by hormones and metabolites that change in response to feeding state 1 . If an energy state persists, adaptive control mechanisms increasingly influence nutrient metabolism. This is exemplified by adaptation of liver metabolism to fasting, wherein a network of nutrient-and hormoneresponsive transcriptional complexes act in tandem with epigenetic changes to drive metabolic rewiring coupled to changes in fuel availability 2-6 . Understanding how feeding

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

“…The limited studies investigating the epigenetic effects of dietary interventions in the pancreas mainly pertain to histone acetylation changes. According to one study, 6 days of TRF (12-h fasting/feeding) in mice enhances GSIS in isolated islets without affecting body weight (Wortham et al, 2019) and is accompanied by histone acetylation of pancreatic islets during the re-feeding period. This epigenetic modulation takes place at sites occupied by the HDM LSD1 (KDM1A), which silences enhancers by removing mono-and dimethyl marks from H3K4 and is implicated in pancreatic endocrine cell development (Vinckier et al, 2020).…”

Metabolism as a central regulator of β‐cell chromatin state

“…DNA demethylation can occur passively or actively via oxidation of the methyl residues on cytosines, generating 5-hydroxymethylcytosine (5hmC); active oxidation is catalyzed by the ten-eleven translocation (TET) family of enzymes which require a-KG and reduced iron (Fe(II)) [92][93][94]. Demethylation of histone residues by lysine-specific demethylases (KDMs) on the other hand is accomplished by two classes of enzymes: lysine-specific demethylases that use FAD as a co-factor, and by Jumonji C (JmjC) domain demethylases that require a-KG and Fe(II) [46,95,96].…”

“…b-cell metabolism and thus levels of acetyl-CoA, NAD + / NADH, SAM, FAD, and a-KG are inextricably tied to insulin secretion in response to nutrient levels. Conditions of nutrient deprivation, chronic nutrient excess, or imbalance likely have a significant impact on b-cell gene expression via the chromatin state, although this is only beginning to be explored [46]. During T2D development, it may occur that chronic nutrient excess induces initial overabundance of certain metabolites, followed by eventual mitochondrial failure, and relative depletion of acetyl-CoA, a-KG, and NAD + .…”

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

“…Chromatin modifications act as a potential link between environmental factors and gene expression changes in β-cells 28,29 . Accordingly, H3K27ac in islet chromatin regulatory domains is correlated with acute glucose-induced gene expression changes 30,31 , and demethylation of DNA and H3K27 are linked to gene activation in T2D 26,32 . Here, we show that H3K4me3 enrichment in mature βcell chromatin corresponds with transcription of critical b-cell genes, and that it is reduced in T2D.…”