Diabetes-associated MYT1 and ST18 genes regulate human beta cell insulin secretion and survival via other diabetes risk genes
Date: | September 2026 |
PMCID: | |
Category: | N/A |
Authors: | Ruiying Hu, Nala Hamilton, Yu Wang, Xin Tong, Mahircan Yagan, Prasanna K Dadi, Cristina Harmelink, Teri D Doss, Jinhua Liu, Yanwen Xu, Alan J Simmons, Ken S Lau, Roland Stein, Appakalai N Balamurugan, Irina Kaverina, Katie C Coate, David A Jacobson, Qi Liu, Guoqiang Gu |
Abstract: |
|
Aims/hypothesis: Genetic and environmental factors work together to cause islet beta cell failure, leading to type 2 diabetes. How these factors are integrated to regulate beta cells remains largely unclear. Based on our previous findings that the family of myelin transcription factors (MYT TFs; including 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 type 2 diabetes, we postulate that these factors prevent human beta cell failure under normal physiological conditions 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 conditions 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 gene sets related to 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 reduced glucose-stimulated Ca2+ influx in beta cells. In addition, the MYT1- and ST18-regulated genes were enriched for type-2-diabetes-associated loci, with an enrichment of 2.05-fold relative to the random distribution of beta cell-expressed genes.
Conclusions/interpretation: The MYT TFs complement each other to integrate genetic and environmental factors to prevent beta cell failure and type 2 diabetes, with their major effects exerted on beta cell viability and/or Ca2+ influx.
Acknowledgements:
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.
The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:
Project Number: | Awardee Organization |
U54CA274374 | Fred Hutchinson Cancer Center |
U54CA274375 | Houston Methodist Research Institute |
U54CA274370 | Johns Hopkins University |
U54CA274371 | UT MD Anderson Cancer Center |
U54CA274367 | Vanderbilt University Medical Center |
Comments