Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes

A. S. Axelsson, T. Mahdi, H. A. Nenonen, T. Singh, S. Hänzelmann, A. Wendt, A. Bagge, T. M. Reinbothe, J. Millstein, X. Yang, B. Zhang, E. G. Gusmao, L. Shu, M. Szabat, Y. Tang, J. Wang, S. Salö, L. Eliasson, I. Artner, M. Fex, J. D. Johnson, C. B. Wollheim, J.M.J. Derry, B. Mecham, P. Spégel, H. Mulder, I.G. Costa, E. Zhang and A. H. Rosengren ()
Additional contact information
A. S. Axelsson: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
T. Mahdi: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
H. A. Nenonen: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
T. Singh: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
S. Hänzelmann: Institute of Biomedical Engineering, RWTH Aachen University Hospital
A. Wendt: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
A. Bagge: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
T. M. Reinbothe: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
J. Millstein: Sage Bionetworks
X. Yang: Sage Bionetworks
B. Zhang: Sage Bionetworks
E. G. Gusmao: Institute of Biomedical Engineering, RWTH Aachen University Hospital
L. Shu: University of California
M. Szabat: Diabetes Research Group, Life Sciences Institute, University of British Columbia
Y. Tang: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
J. Wang: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
S. Salö: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
L. Eliasson: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
I. Artner: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
M. Fex: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
J. D. Johnson: Diabetes Research Group, Life Sciences Institute, University of British Columbia
C. B. Wollheim: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
J.M.J. Derry: Sage Bionetworks
B. Mecham: Trialomics
P. Spégel: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
H. Mulder: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
I.G. Costa: Institute of Biomedical Engineering, RWTH Aachen University Hospital
E. Zhang: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
A. H. Rosengren: Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.

Date: 2017
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DOI: 10.1038/ncomms15652

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