Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Ildem Akerman, Miguel Angel Maestro, Elisa De Franco, Vanessa Grau, Sarah Flanagan, Javier García-Hurtado, Gerhard Mittler, Philippe Ravassard, Lorenzo Piemonti, Sian Ellard, Andrew T. Hattersley, Jorge Ferrer

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number108981
JournalCell Reports
Issue number2
Publication statusPublished - Apr 13 2021


  • GLIS3
  • HIP
  • INS promoter
  • mouse model
  • neonatal diabetes
  • regulatory element

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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