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

Peiris, Heshan ; Park, Sangbin ; Louis, Shreya ; Gu, Xueying ; Lam, Jonathan Y. ; Asplund, Olof LU ; Ippolito, Gregory C. ; Bottino, Rita ; Groop, Leif LU and Tucker, Haley , et al. (2018) In Nature Communications 9(1).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
9
issue
1
article number
3855
publisher
Nature Publishing Group
external identifiers
  • scopus:85053726357
  • pmid:30242153
ISSN
2041-1723
DOI
10.1038/s41467-018-06249-3
language
English
LU publication?
yes
id
6d121d04-7a2e-4c75-88a4-bb2c9b7c8b5a
date added to LUP
2018-10-08 13:26:10
date last changed
2024-04-15 13:04:08
@article{6d121d04-7a2e-4c75-88a4-bb2c9b7c8b5a,
  abstract     = {{<p>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.</p>}},
  author       = {{Peiris, Heshan and Park, Sangbin and Louis, Shreya and Gu, Xueying and Lam, Jonathan Y. and Asplund, Olof and Ippolito, Gregory C. and Bottino, Rita and Groop, Leif and Tucker, Haley and Kim, Seung K.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Discovering human diabetes-risk gene function with genetics and physiological assays}},
  url          = {{http://dx.doi.org/10.1038/s41467-018-06249-3}},
  doi          = {{10.1038/s41467-018-06249-3}},
  volume       = {{9}},
  year         = {{2018}},
}