Diabetes-associated MYT1 and ST18 regulate human beta-cell insulin secretion and survival via other diabetes-risk genes
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Aims/hypothesis
Genetic and environmental factors work together to cause islet beta-cell failure, leading to type 2 diabetes (T2D). How these factors are integrated to regulate beta cells remains largely unclear. Based on our previous findings that the family of Myelin transcription factors (MYT1, MYT1L, and ST18) prevents mouse beta-cell failure by repressing the overactivation of stress response, their regulation by obesity-related nutrition signals in human beta cells, and their association with T2D, we postulate that these factors prevent human beta-cell failure under normal physiology and obesity-related stress.
Methods
MYT1 or ST18 were knocked down in primary human beta cells using shRNA. Beta-cell survival, secretory function, and gene expression were examined after islet cells were cultured in vitro or xenotransplanted into mice under normal or obesity-related stress.
Results
In culture, MYT1- knockdown (KD) caused beta-cell death, while ST18- KD compromised glucose-stimulated insulin secretion. Under obesity-induced stress as xenotransplants, ST18- KD also caused beta-cell death. Accordingly, MYT1- KD deregulated several genes and genesets in cell death and cellular stress response, while ST18 -KD deregulated those regulating stress response, mitochondria, and ion channels. Corresponding to these gene expression changes, ST18 -KD reduces glucose-stimulated Ca 2+ influx in beta cells. In addition, the MYT1- and ST18 -regulated genes are enriched for T2D-associated loci, with an enrichment of 2.05-fold relative to random distribution.
Conclusions/interpretation
The MYT TFs complement each other to integrate genetic and environmental factors to prevent beta-cell failure and T2D, with their major effects exerted on beta-cell viability and/or Ca 2+ influx.
Graphical Abstract
Nutrient-responsive transcription factors MYT1 and ST18 regulate human beta-cell survival and secretory functions. Under low metabolic stress, MYT1 regulates cell survival while ST18 regulates insulin secretion. Under high metabolic stress, ST18 also regulates beta-cell survival. MYT1, at least partly, regulates cell survival through stress-related apoptotic processes, while ST18 regulates insulin secretion via Ca 2+ influx.
Research in context summary
Background
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The myelin transcription factors (MYT TFs, including MYT1, MYT1l, and ST18) prevent mouse beta-cell failure by depressing the overactivation of stress-response genes.
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SNPs in all three MYT loci are associated with human type 2 diabetes.
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The expression and nuclear localization of MYT1 and ST18 were increased in primary human beta cells under acute metabolic stress but downregulated in type 2 diabetes.
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The co-knockdown of MYT1 , MYT1L , and ST18 in a human beta-cell line resulted in apoptosis.
Key question
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How does MYT1 or ST18 regulate human beta-cell function and survival?
New findings
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MYT1 prevents human beta-cell death under normal and metabolic stress conditions, corresponding to deregulation of a few genes involved in cell death under cellular stress.
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ST18 promotes insulin secretion under normal physiological conditions by regulating Ca 2+ influx and prevents beta-cell death under metabolic stress.
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The MYT1- and ST18-regulated genes are enriched for type 2 diabetes-risk loci.
Clinical impact
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Regulators of the MYT-TF activities could be explored to delay/prevent beta-cell failure and the development of type 2 diabetes.
