Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.
Author
Akerman, Ildem
Maestro, Miguel Angel
De Franco, Elisa
Grau, Vanessa
Flanagan, Sarah
García-Hurtado, Javier
Mittler, Gerhard
Ravassard, Philippe
Piemonti, Lorenzo
Ellard, Sian
Hattersley, Andrew T.
Ferrer, Jorge
Date
2021-04-13Journal
Cell reportsType
Journal ArticlePublisher
ElsevierDOI
10.1016/j.celrep.2021.108981Rights
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.Metadata
Show full item recordAbstract
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.