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

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Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes
Nature Genetics ( IF 31.7 ) Pub Date : 2023-05-25 , DOI: 10.1038/s41588-023-01397-9
Gaowei Wang _{1,

2} , Joshua Chiou _{1,

2,

3} , Chun Zeng _{1,

2} , Michael Miller ₄ , Ileana Matta _{1,

2} , Jee Yun Han ₄ , Nikita Kadakia _{1,

2} , Mei-Lin Okino _{1,

2} , Elisha Beebe _{1,

2} , Medhavi Mallick _{1,

2} , Joan Camunas-Soler ₅ , Theodore Dos Santos _{6,

7} , Xiao-Qing Dai _{6,

7} , Cara Ellis _{6,

7} , Yan Hang _{8,

9} , Seung K Kim _{8,

9,

10} , Patrick E MacDonald _{6,

7} , Fouad R Kandeel ₁₁ , Sebastian Preissl _{4,

12} , Kyle J Gaulton _{1,

2,

13} , Maike Sander _{1,

2,

13,

14,

15}

Affiliation

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA.
Biomedical Graduate Studies Program, University of California San Diego, La Jolla, CA, USA.
Center for Epigenomics, University of California San Diego, La Jolla, CA, USA.
Department of Bioengineering, Stanford University, Stanford, CA, USA.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
Departments of Medicine and of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
Department of Clinical Diabetes, Endocrinology & Metabolism, City of Hope, Duarte, CA, USA.
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

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.

中文翻译：

将遗传学与跨疾病状态的单细胞多组学测量相结合，确定 2 型糖尿病中 β 细胞功能障碍的机制

功能失调的胰岛β细胞是2型糖尿病（T2D）的一个标志，但目前尚缺乏对其潜在机制（包括基因失调）的全面了解。在这里，我们将单个 β 细胞中染色质可及性、基因表达和功能的测量信息与遗传关联数据整合起来，以提名 T2D 中致病基因的调控变化。利用来自 34 个非糖尿病、T2D 前期和 T2D 供体的染色质可及性数据的机器学习，我们确定了两种转录和功能不同的 β 细胞亚型，它们在 T2D 进展过程中经历了丰度转变。定义亚型的可及染色质富含 T2D 风险变异，表明亚型身份对 T2D 具有因果作用。两种 β 细胞亚型在 T2D 中均表现出应激反应转录程序的激活和功能损伤，这可能是由 T2D 相关代谢环境诱导的。我们的研究结果证明了多模式单细胞测量与机器学习相结合在描述复杂疾病机制方面的力量。

更新日期：2023-05-26

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