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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.

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


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.

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