Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene
Summary: 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 sho...
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doaj-282fb6a0abd54a338e19484f6b2bb3052021-04-16T04:53:27ZengElsevierCell Reports2211-12472021-04-01352108981Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin geneIldem Akerman0Miguel Angel Maestro1Elisa De Franco2Vanessa Grau3Sarah Flanagan4Javier García-Hurtado5Gerhard Mittler6Philippe Ravassard7Lorenzo Piemonti8Sian Ellard9Andrew T. Hattersley10Jorge Ferrer11Institute of Metabolism and Systems Research (IMSR), Medical School, University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham, UK; Corresponding authorCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Centro de Investigación Biomédica en red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, SpainInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UKCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Centro de Investigación Biomédica en red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, SpainInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UKCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Centro de Investigación Biomédica en red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, SpainMax-Planck Institute for Immunobiology and Epigenetics, Freiburg, GermanyINSERM, CNRS, Paris Brain Institute - Hôpital Pitié-Salpêtrière, Paris, FranceDiabetes Research Institute, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, ItalyInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UKInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UKCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Centro de Investigación Biomédica en red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721002953INS promoterregulatory elementmouse modelneonatal diabetesGLIS3HIP |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene Cell Reports INS promoter regulatory element mouse model neonatal diabetes GLIS3 HIP |
author_facet |
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 |
author_sort |
Ildem Akerman |
title |
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene |
title_short |
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene |
title_full |
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene |
title_fullStr |
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene |
title_full_unstemmed |
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene |
title_sort |
neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2021-04-01 |
description |
Summary: 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. |
topic |
INS promoter regulatory element mouse model neonatal diabetes GLIS3 HIP |
url |
http://www.sciencedirect.com/science/article/pii/S2211124721002953 |
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