Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes

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Item Type:	Article
Title:	Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes
Creators Name:	Wang, G., Chiou, J., Zeng, C., Miller, M., Matta, I., Han, J.Y., Kadakia, N., Okino, M.L., Beebe, E., Mallick, M., Camunas-Soler, J., Dos Santos, T., Dai, X.Q., Ellis, C., Hang, Y., Kim, S.K., MacDonald, P.E., Kandeel, F.R., Preissl, S., Gaulton, K.J. and Sander, M.
Abstract:	Dysfunctional pancreatic islet beta cells are a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of the underlying mechanisms, including gene dysregulation, is lacking. Here we integrate information from measurements of chromatin accessibility, gene expression and function in single beta cells with genetic association data to nominate disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 nondiabetic, pre-T2D and T2D donors, we identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift during T2D progression. Subtype-defining accessible chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both beta cell subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is probably induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for characterizing mechanisms of complex diseases.
Keywords:	Chromatin, Type 2 Diabetes Mellitus, Gene Expression Regulation, Insulin-Secreting Cells, Multiomics
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	55
Number:	6
Page Range:	984-994
Date:	June 2023
Additional Information:	Copyright © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Official Publication:	https://doi.org/10.1038/s41588-023-01397-9
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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