Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene
dc.contributor.author | Akerman, I | |
dc.contributor.author | Maestro, MA | |
dc.contributor.author | De Franco, E | |
dc.contributor.author | Grau, V | |
dc.contributor.author | Flanagan, S | |
dc.contributor.author | García-Hurtado, J | |
dc.contributor.author | Mittler, G | |
dc.contributor.author | Ravassard, P | |
dc.contributor.author | Piemonti, L | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Ferrer, J | |
dc.date.accessioned | 2021-05-12T15:31:41Z | |
dc.date.issued | 2021-04-13 | |
dc.description.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. | en_GB |
dc.description.sponsorship | Birmingham Fellowship Programme | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.description.sponsorship | Academy of Medical Sciences | en_GB |
dc.description.sponsorship | Ministerio de Ciencia e Innovación | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.description.sponsorship | European Research Council (ERC) | en_GB |
dc.description.sponsorship | European Union FP6 | en_GB |
dc.description.sponsorship | National Institute for Health Research (NIHR) | en_GB |
dc.description.sponsorship | Royal Society | en_GB |
dc.identifier.citation | Vol. 35 (2), article 108981 | en_GB |
dc.identifier.doi | 10.1016/j.celrep.2021.108981 | |
dc.identifier.grantnumber | 20/0006136 | en_GB |
dc.identifier.grantnumber | SBF006\1140 | en_GB |
dc.identifier.grantnumber | BFU2014-54284-R | en_GB |
dc.identifier.grantnumber | RTI2018-095666-B-I00 | en_GB |
dc.identifier.grantnumber | MR/L02036X/1 | en_GB |
dc.identifier.grantnumber | WT101033 | en_GB |
dc.identifier.grantnumber | 789055 | en_GB |
dc.identifier.grantnumber | 518153 | en_GB |
dc.identifier.grantnumber | 19/005971 | en_GB |
dc.identifier.grantnumber | WT098395/Z/12/Z | en_GB |
dc.identifier.grantnumber | 105636/Z/14/Z | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/125654 | |
dc.language.iso | en | en_GB |
dc.publisher | Cell Press | en_GB |
dc.rights | © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) | en_GB |
dc.subject | INS promoter | en_GB |
dc.subject | regulatory element | en_GB |
dc.subject | mouse model | en_GB |
dc.subject | neonatal diabetes | en_GB |
dc.subject | GLIS3 | en_GB |
dc.title | Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2021-05-12T15:31:41Z | |
dc.identifier.issn | 2211-1247 | |
dc.description | This is the final version. Available on open access from Cell Press via the DOI in this record | en_GB |
dc.identifier.journal | Cell Reports | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_GB |
dcterms.dateAccepted | 2021-03-23 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2021-04-13 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2021-05-12T15:23:51Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2021-05-12T15:32:10Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)