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PLoS Genet. 2016 Dec 9;12(12):e1006466. doi: 10.1371/journal.pgen.1006466. eCollection 2016 Dec.

The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets.

Author information

1
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
2
Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
3
Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.
4
Sage Bionetworks, Seattle, Washington.
5
Institute for Systems Biology, Seattle, Washington.
6
Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.

Abstract

Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced β-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote β-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. β-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates β-cell proliferation in both mouse and human islets.

PMID:
27935966
PMCID:
PMC5147809
DOI:
10.1371/journal.pgen.1006466
[Indexed for MEDLINE]
Free PMC Article

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