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Updated: May 23, 2025
A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Diabetes-associated MYT1 and MYT3 regulate human β-cell insulin secretion and survival via other diabetes-risk genes
Ruiying Hu1, Mahircan Yagan1, Yu Wang2
1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Abstract:
Genetic and environmental factors together cause islet β-cell failure, leading to Type 2 diabetes (T2D). Yet how they integrate to regulate β-cells remains largely unclear. Here, we examined how two members of the Myelin transcription factor family (MYT1, 2, and 3) prevent human β-cell failure under obesity-related stress. We have reported that obesity-related nutrient levels induce these factors. They prevent β-cell failure in mouse islets and human β-cell lines. Their variants are all associated with human T2D, and their downregulation accompanies β-cell dysfunction. By knocking down MYT1 or MYT3 separately in primary human donor islets, we show here that they have overlapping but distinct functions. Under normal culture conditions, MYT1-knockdown (KD) causes β-cell death, while MYT3-KD compromises glucose-stimulated insulin secretion. Under obesity-induced metabolic stress in vivo, MYT3-KD also causes β-cell death. Accordingly, these TFs regulate common and unique genes, with MYT1-KD de-regulating several genes in cell death and Ca2+ binding, while MYT3-KD de-regulating genes involved in mitochondria, ER, etc. Intriguingly, the MYT1 and MYT3-regulated genes are enriched for T2D-associated genes. These findings suggest that the MYT TFs complement each other to serve as a node that integrates genetic and environmental factors to prevent β-cell failure and T2D.
Insights
Myelin transcription factors (MYT1 and MYT3) are crucial for preventing human islet beta-cell failure and Type 2 diabetes (T2D). Their distinct roles in cell survival and insulin secretion highlight their importance in integrating genetic and environmental factors for beta-cell health.
Area of Science:
- Endocrinology and Metabolism
- Molecular Biology
- Genetics
Background:
- Genetic and environmental factors contribute to islet beta-cell failure, a hallmark of Type 2 diabetes (T2D).
- The Myelin transcription factor (MYT) family, including MYT1, MYT2, and MYT3, has been implicated in T2D risk, with their downregulation associated with beta-cell dysfunction.
- Obesity-related nutrient levels are known to influence MYT factor levels and nuclear localization, suggesting a role in integrating nutritional signals.
Purpose of the Study:
- To investigate the specific roles of MYT1 and MYT3 in preventing human islet beta-cell failure under normal and obesity-related stress conditions.
- To elucidate how MYT1 and MYT3 regulate gene expression and cellular functions in primary human beta-cells.
- To understand the integration of genetic and environmental factors by MYT transcription factors in the context of T2D.
Main Methods:
- Knockdown (KD) of MYT1 or MYT3 in primary human donor islets.
- Assessment of beta-cell survival, insulin secretion, and gene expression under normal and obesity-induced metabolic stress.
- Analysis of MYT-regulated genes for enrichment of T2D-associated genes.
Main Results:
- MYT1 KD led to beta-cell death under normal conditions, while MYT3 KD impaired glucose-stimulated insulin secretion.
- MYT3 KD resulted in beta-cell death under obesity-induced metabolic stress.
- MYT1 and MYT3 regulate distinct sets of genes involved in cell death, calcium binding, mitochondria, and ER, with significant overlap.
- Genes regulated by MYT1 and MYT3 are enriched for T2D-associated genes.
Conclusions:
- MYT1 and MYT3 play complementary and distinct roles in maintaining human beta-cell function and survival.
- These MYT transcription factors act as critical integrators of genetic and environmental factors to prevent beta-cell failure.
- Targeting MYT transcription factor activities presents a potential therapeutic strategy for attenuating beta-cell failure and T2D risk.
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