ArticleCell reports2021
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.
Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Identification of distinct functions of GLIS3 in β-cell generation critical to prevention of neonatal diabetes.bioRxiv : the preprint server for biology · 2026Article
- Semi-supervised Bayesian integration of multiple spatial proteomics datasets.PLoS computational biology · 2025Article
- Masterful macrophages: understanding and targeting activation dysfunction in diabetic wounds.Burns & trauma · 2025Review
- Article
- Review
- Article
- Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers.Nature communications · 2022Article
- MafA Regulation in β-Cells: From Transcriptional to Post-Translational Mechanisms.Biomolecules · 2022Review
- Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction.International journal of molecular sciences · 2022Review
- Review
- Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice.JCI insight · 2021Article
- Fresh insight into neonatal diabetes mutations.Nature reviews. Endocrinology · 2021Article
- Transcription factor GLIS3: Critical roles in thyroid hormone biosynthesis, hypothyroidism, pancreatic beta cells and diabetes.Pharmacology & therapeutics · 2020Review
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12 authors at 8 institutions in 5 countries.
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Abstract
Despite the central role of chromosomal context in gene transcription, human noncoding DNA variants are generally studied outside of their genomic location. This limits our understanding of disease-causing regulatory variants. INS promoter mutations cause recessive neonatal diabetes. We show that all INS promoter point mutations in 60 patients disrupt a CC dinucleotide, whereas none affect other elements important for episomal promoter function. To model CC mutations, we humanized an ∼3.1-kb region of the mouse Ins2 gene. This recapitulated developmental chromatin states and cell-specific transcription. A CC mutant allele, however, abrogated active chromatin formation during pancreas development. A search for transcription factors acting through this element revealed that another neonatal diabetes gene product, GLIS3, has a pioneer-like ability to derepress INS chromatin, which is hampered by the CC mutation. Our in vivo analysis, therefore, connects two human genetic defects in an essential mechanism for developmental activation of the INS gene.
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