Discovering human diabetes-risk gene function with genetics and physiological assays

Heshan Peiris, Sangbin Park, Shreya Louis, Xueying Gu, Jonathan Y. Lam, Olof Asplund, Gregory C. Ippolito, Rita Bottino, Leif Groop, Haley Tucker and Seung K. Kim ()
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Heshan Peiris: Stanford University School of Medicine
Sangbin Park: Stanford University School of Medicine
Shreya Louis: Stanford University School of Medicine
Xueying Gu: Stanford University School of Medicine
Jonathan Y. Lam: Stanford University School of Medicine
Olof Asplund: Lund University Diabetes Centre
Gregory C. Ippolito: University of Texas at Austin
Rita Bottino: Allegheny Health Network
Leif Groop: Lund University Diabetes Centre
Haley Tucker: University of Texas at Austin
Seung K. Kim: Stanford University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.

Date: 2018
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DOI: 10.1038/s41467-018-06249-3

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