Dissecting the Heterogeneity of Human Islet Stress Responses in Type 2 Diabetes
[Technical Report, Annual Report]
The Jackson Laboratory
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The overall objective of this project is to dissect the genetic regulation of islet stress responses and to determine how genetic variants, including those associated with type 2 diabetes T2D SNPs, modulate these responses to contribute to islet dysfunction and T2D pathogenesis. This project will address significant gaps in our knowledge of the genetic and cellular heterogeneity of T2D by 1 defining the precise transcriptomic and epigenomic alterations in islets associated with diabetogenic oxidative and inflammatory stressors 2 determining how each islet cell type responds to each stressor 3 identifying individual genetic variants, particularly T2D SNPs, that modulate these responses to increase or decrease diabetes susceptibility and 4 testing whether the genes and pathways induced by these stressors are compensatoryprotective or pathogenic. To date, we have found that islet cytokine and oxidative stress induces changes in the use andor activity of 10,000 putative regulatory elements and expression of 1500 genes, including 206 regulatory elements containing T2D SNPs and 171 putative T2D effector genes. While each stressor clearly elicited distinct transcriptional programs, epigenetic signatures from differentially accessible sites shared between stressors suggest that both may poise islets for dedifferentiation. CRISPRCas9 knockout of 84 and 18 genes altered MIN6 beta cell viability or insulin content, respectively, suggesting their modulation by these stressors is detrimental to beta cell health and function. Efforts continue to link T2D SNPs and other genetic variants to altered islet stress responses. Together, these results are building the foundation for a better understanding of the genetic programming of islet cytokine and oxidative stress responses and insights into the molecular mechanisms underlying T2D genetic risk.
- Medicine and Medical Research