Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06249-3
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Funding
- Stanford Child Health Research Institute [UL1 TR001085]
- American Diabetes Association [1-16-PDF-086]
- National Institute of Health [F32CA110624, R01CA31534]
- Cancer Prevention Research Institute of Texas [RP120459]
- Marie Betzner Morrow Centennial Endowment
- NIH [DK104211, DK107507, DK102612, P30 DK116074, DK108817]
- Juvenile Diabetes Research Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- H. L. Snyder Medical Foundation
- Islet Research Core of the Stanford Diabetes Research Center
- AMP T2D consortium [UO1DK105554]
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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.
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