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

Axelsson, Annika LU ; Mahdi, T LU ; Nenonen, H A LU ; Singh, Tania LU ; Hänzelmann, S LU ; Wendt, A LU ; Bagge, Annika LU ; Reinbothe, T M LU ; Millstein, J and Yang, X LU , et al. (2017) In Nature Communications 8. p.15652-15652
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 Ca(2+)-influx and β-cell exocytosis. SOX5 overexpression reverses the expression... (More)

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 Ca(2+)-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.

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keywords
Journal Article
in
Nature Communications
volume
8
pages
15652 - 15652
publisher
Nature Publishing Group
external identifiers
  • scopus:85020265594
ISSN
2041-1723
DOI
10.1038/ncomms15652
language
English
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yes
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2d025ae1-70f7-4e53-80c9-06520c23440e
date added to LUP
2017-06-13 12:47:15
date last changed
2017-09-13 03:00:03
@article{2d025ae1-70f7-4e53-80c9-06520c23440e,
  abstract     = {<p>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 Ca(2+)-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.</p>},
  author       = {Axelsson, Annika and Mahdi, T and Nenonen, H A and Singh, Tania and Hänzelmann, S and Wendt, A and Bagge, Annika and Reinbothe, T M and Millstein, J and Yang, X and Zhang, B and Gusmao, E G and Shu, L and Szabat, M and Tang, Y and Wang, Jinling and Salö, Sofia and Eliasson, L and Artner, I and Fex, M and Johnson, J D and Wollheim, C B and Derry, J M J and Mecham, B and Spégel, P and Mulder, H and Costa, Ivan G and Zhang, E and Rosengren, A H},
  issn         = {2041-1723},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {06},
  pages        = {15652--15652},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes},
  url          = {http://dx.doi.org/10.1038/ncomms15652},
  volume       = {8},
  year         = {2017},
}