ArticlePLoS genetics2016
The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Harmine selectively enhances human beta cell identity markers and function via protein kinase A pathways.Diabetologia · 2026Article
- Genome-wide cell type-specific and sex-specific transcriptional dysregulation in the islet of Langerhans underlies islet dysfunction in Down syndrome-related diabetes.bioRxiv : the preprint server for biology · 2026Article
- Mechanisms inducing differentiation of adult islet progenitor-like cells into functional islet-like organoids.Frontiers in transplantation · 2026Article
- Dual role of neuroplastin in pancreatic β cells: Regulating insulin secretion and promoting islet inflammation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types.American journal of physiology. Regulatory, integrative and comparative physiology · 2024Article
- Review
- Article
- Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines.Cell genomics · 2022Article
- Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism.Nature genetics · 2022Article
- Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells.The Journal of clinical investigation · 2022Article
- Article
- Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.iScience · 2022Article
- Dynamic changes in β-cell [CaMolecular metabolism · 2022Article
- Integrated bioinformatics analysis reveals novel key biomarkers in diabetic nephropathy.SAGE open medicine · 2022Article
- The Pancreatic ß-cell Response to Secretory Demands and Adaption to Stress.Endocrinology · 2021Review
- Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation.The Journal of clinical investigation · 2021Article
- INFIMA leverages multi-omics model organism data to identify effector genes of human GWAS variants.Genome biology · 2021Article
- TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell.Metabolites · 2021Article
- Near-UV Light Induced ROS Production Initiates Spatial CaInternational journal of molecular sciences · 2021Article
- Transcriptional mechanisms of pancreatic β-cell maturation and functional adaptation.Trends in endocrinology and metabolism: TEM · 2021Review
Corrections and comments
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Authors and funding
21 authors.
Funding
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.
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Registered trials
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