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

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

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

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dc.contributor.author Akerman, Ildem
dc.contributor.author Maestro, Miguel Ángel
dc.contributor.author De Franco, Elisa
dc.contributor.author Grau, Vanessa
dc.contributor.author Flanagan, Sarah
dc.contributor.author García-Hurtado, Javier
dc.contributor.author Mittler, Gerhard
dc.contributor.author Ravassard, Philippe
dc.contributor.author Piemonti, Lorenzo
dc.contributor.author Ellard, Sian
dc.contributor.author Hattersley, Andrew T.
dc.contributor.author Ferrer, Jorge
dc.date.accessioned 2021-05-28T06:24:42Z
dc.date.available 2021-05-28T06:24:42Z
dc.date.issued 2021
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.
dc.description.sponsorship This research was supported by the Birmingham Fellowship Programme, RD Lawrence Fellowship (Diabetes UK, 20/0006136), and Academy of Medical Sciences Springboard (SBF006\1140) to I.A. Other main funding sources (to J.F.) are Ministerio de Ciencia e Innovación (BFU2014-54284-R and RTI2018-095666-B-I00), Medical Research Council (MR/L02036X/1), a Wellcome Trust Senior Investigator Award (WT101033), European Research Council Advanced Grant (789055), and FP6-LIFESCIHEALTH 518153. E.D.F. is a Diabetes UK RD Lawrence Fellow (19/005971). A.T.H. and S.E. are the recipients of a Wellcome Trust Senior Investigator award (WT098395/Z/12/Z). S.E.F. has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z). Human islets for research were supported by the Juvenile Diabetes Research Foundation (2-RSC-2019-724-I-X). Work in CRG was supported by the CERCA Programme, Generalitat de Catalunya, and Centro de Excelencia Severo Ochoa (SEV-2015-0510). CRG acknowledges the support of the Spanish Ministry of Science and Innovation to the EMBL partnership
dc.format.mimetype application/pdf
dc.identifier.citation Akeman I, Maestro MA, De Franco E, Grau V, Flanagan S, García-Hurtado J et al. Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene. Cell Rep. 2021 Apr 13;35(2):108981. DOI: 10.1016/j.celrep.2021.108981
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2021.108981
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/47678
dc.language.iso eng
dc.publisher Elsevier
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-54284-R
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/789055
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP6/518153
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.other Infants nadons -- Malalties
dc.subject.other Diabetis
dc.subject.other Insulina
dc.subject.other Genètica
dc.title Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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