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

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

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.

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Chromosome Mapping
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Gene Expression Regulation
  • Genetic Linkage
  • Genome
  • Genome-Wide Association Study
  • Humans
  • Insulin / genetics*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Obese
  • NFATC Transcription Factors / biosynthesis
  • NFATC Transcription Factors / genetics*
  • Promoter Regions, Genetic

Substances

  • Insulin
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Nfatc2 protein, mouse