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

Nature Communications
Heshan PeirisSeung K Kim

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.

References

Jul 23, 2003·The Journal of Biological Chemistry·Laura SheuHerbert Y Gaisano
Apr 11, 2006·Proceedings of the National Academy of Sciences of the United States of America·Changjun ZhuWei Jiang
Nov 18, 2006·Proceedings of the National Academy of Sciences of the United States of America·Ruud F G ToonenMatthijs Verhage
Mar 3, 2007·Annals of the New York Academy of Sciences·Leonard D ShultzDale L Greiner
Feb 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Manuela UdaAntonio Cao
Aug 7, 2009·Nature·Vijay G SankaranStuart H Orkin
Dec 8, 2009·Science·Anders H RosengrenErik Renström
Jan 12, 2010·Developmental Cell·Maija SlaidinaPierre Léopold
Feb 18, 2010·Proceedings of the National Academy of Sciences of the United States of America·Arndt PechsteinVolker Haucke
Jun 29, 2010·Nature Genetics·Benjamin F VoightUNKNOWN GIANT Consortium
Aug 7, 2010·Aging·Aaron T Haselton, Yih-Woei C Fridell
Oct 5, 2010·Neuroreport·Orsolya KréneiszDaniel K Mulkey
Jun 2, 2012·Methods : a Companion to Methods in Enzymology·Jon-Matthew BeltonJob Dekker
Aug 14, 2012·Nature Genetics·Andrew P MorrisUNKNOWN DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Sep 21, 2013·Disease Models & Mechanisms·Asha SethInês Barroso
Mar 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Gregory C IppolitoHaley O Tucker
Sep 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·João FadistaLeif Groop
Mar 17, 2015·Genes·Rashmi B Prasad, Leif Groop
Mar 18, 2015·Journal of Cellular and Molecular Medicine·Janneke HilderinkAart van Apeldoorn
May 6, 2015·The Journal of Clinical Investigation·Anindita BasakVijay G Sankaran
Oct 24, 2015·The Journal of Endocrinology·Sof AndrikopoulosGrant Morahan
Nov 20, 2015·Molecular Endocrinology·Ryan K MitchellGuy A Rutter
Mar 16, 2016·Molecular Metabolism·Amanda M AckermannKlaus H Kaestner
Apr 8, 2016·Disease Models & Mechanisms·Ronald W Alfa, Seung K Kim
Sep 27, 2016·Cell Metabolism·Åsa SegerstolpeRickard Sandberg
Jun 2, 2017·Diabetes·Robert A ScottUNKNOWN DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Jun 28, 2017·Blood Cells, Molecules & Diseases·Swee Lay Thein

❮ Previous
Next ❯

Citations

Oct 28, 2019·Bioscience Reports·Jiawei YinFengyuan Che
Sep 13, 2019·Nature Communications·Alexander TeumerAnna Köttgen
Nov 23, 2019·International Journal for Equity in Health·Edwin Nieblas-BedollaFrances K Barg
Jul 23, 2020·Nature Metabolism·Krissie TellezSeung K Kim
Jan 20, 2021·The Journal of Clinical Investigation·Ming LiuPeter Arvan
Jan 16, 2021·Genes & Development·Romina J BevacquaSeung K Kim
Apr 25, 2021·Nature Communications·Romina J BevacquaSeung K Kim
Apr 20, 2021·Frontiers in Cell and Developmental Biology·Gloria BarbaraniAntonella E Ronchi
May 6, 2021·Diabetes·Mollie S H FriedlanderRomina J Bevacqua
Apr 13, 2021·Endocrine Reviews·John T WalkerAlvin C Powers

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
flow cytometry
RNA-seq
ELISA
transfection
FACS
chip

Software Mentioned

RSEM
Ensembl
FlowJo
Fastqc
Bowtie
DEseq2
TreeStar
GSEA

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.