Show simple item record

Primate-specific ZNF808 is essential for pancreatic development in humans

dc.contributor.authorDe Franco, E
dc.contributor.authorOwens, NDL
dc.contributor.authorMontaser, H
dc.contributor.authorWakeling, MN
dc.contributor.authorSaarimäki-Vire, J
dc.contributor.authorTriantou, A
dc.contributor.authorIbrahim, H
dc.contributor.authorBalboa, D
dc.contributor.authorCaswell, RC
dc.contributor.authorJennings, RE
dc.contributor.authorKvist, JA
dc.contributor.authorJohnson, MB
dc.contributor.authorMuralidharan, S
dc.contributor.authorEllard, S
dc.contributor.authorWright, CF
dc.contributor.authorMaddirevula, S
dc.contributor.authorAlkuraya, FS
dc.contributor.authorHanley, NA
dc.contributor.authorFlanagan, SE
dc.contributor.authorOtonkoski, T
dc.contributor.authorHattersley, AT
dc.contributor.authorImbeault, M
dc.date.accessioned2023-07-25T12:35:34Z
dc.date.issued2023-11-16
dc.date.updated2023-07-25T10:53:32Z
dc.description.abstractIdentifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes not shared with all other mammals. Here we report the identification of homozygous loss-of-function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein (KZFPs) family, a large and rapidly evolving group of epigenetic silencers that target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of regulatory potential contained in the primate-specific transposable elements it represses during early pancreas development. This leads to inappropriate specification of cell fate with induction of genes associated with liver identity. Our results highlight the essential role of ZNF808 for pancreatic development in humans and the contribution of primate-specific regions of the human genome to disease. This is the first report of loss of a primate-specific gene causing a congenital developmental disease.en_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.description.sponsorshipDiabetes UKen_GB
dc.description.sponsorshipEFSDen_GB
dc.description.sponsorshipRoyal Societyen_GB
dc.description.sponsorshipResearch Englanden_GB
dc.description.sponsorshipAcademy of Sciencesen_GB
dc.description.sponsorshipMedical Research Council (MRC)en_GB
dc.description.sponsorshipAcademy of Finlanden_GB
dc.description.sponsorshipNovo Nordisk Foundationen_GB
dc.description.sponsorshipSigrid Juselius Foundationen_GB
dc.description.sponsorshipFoundation for Education and European Culture (IPEP)en_GB
dc.description.sponsorshipCambridge Trusten_GB
dc.description.sponsorshipEuropean Molecular Biology Organizationen_GB
dc.description.sponsorshipKing Salman Center for Disability Researchen_GB
dc.identifier.citationVol. 55, pp. 2075–2081en_GB
dc.identifier.doi10.1038/s41588-023-01565-x
dc.identifier.grantnumber224600/Z/21/Zen_GB
dc.identifier.grantnumberWT098395/Z/12/Zen_GB
dc.identifier.grantnumber105636/Z/14/Zen_GB
dc.identifier.grantnumber19/005971en_GB
dc.identifier.grantnumber20/0006263en_GB
dc.identifier.grantnumber206688/Z/17/Zen_GB
dc.identifier.grantnumberMR/000638/1en_GB
dc.identifier.grantnumberMR/S036121/1en_GB
dc.identifier.grantnumber312437en_GB
dc.identifier.grantnumber0057286en_GB
dc.identifier.grantnumberALTF 295-2019en_GB
dc.identifier.grantnumberRG-2022-010en_GB
dc.identifier.urihttp://hdl.handle.net/10871/133654
dc.identifierORCID: 0000-0002-1437-7891 (De Franco, Elisa)
dc.language.isoenen_GB
dc.publisherNature Researchen_GB
dc.relation.urlhttps://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/
dc.relation.urlhttps://github.com/owensnick/ZNF808Genomics.jl
dc.relation.urlhttps://doi.org/10.5281/zenodo.8375708
dc.rights© The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en_GB
dc.titlePrimate-specific ZNF808 is essential for pancreatic development in humansen_GB
dc.typeArticleen_GB
dc.date.available2023-07-25T12:35:34Z
dc.identifier.issn1546-1718
dc.descriptionThis is the final version. Available on open access from Nature Research via the DOI in this recorden_GB
dc.descriptionData availability: Clinical and genotype data are available only through collaboration as this can be used to identify individuals and so cannot be made openly available. Requests for collaboration will be considered following an application to the Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/). Contact by email should be directed to A. Hattersley (A.T.Hattersley@exeter.ac.uk). All requests for access to data will be responded to within 28 days. Transcriptomic and epigenomic data for WT and ZNF808 KO are available from the NCBI Gene Expression Omnibus under accession GSE205164. Source data are provided with this paper.en_GB
dc.descriptionCode availability: Code and software versions used to analyze the data presented are indicated in the Methods and provided in https://github.com/owensnick/ZNF808Genomics.jl with persistent Zenodo https://doi.org/10.5281/zenodo.8375708.
dc.identifier.journalNature Geneticsen_GB
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2023-10-10
dcterms.dateSubmitted2023-02-14
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2023-10-10
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2023-07-25T10:53:35Z
refterms.versionFCDAM
refterms.dateFOA2023-12-15T16:15:23Z
refterms.panelAen_GB


Files in this item

Name:
s41588-023-01565-x.pdf
Size:
12.03Mb
Format:
PDF
Description:
Primate-specific ZNF808 is ...
View/Open

This item appears in the following Collection(s)

Show simple item record

© The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Except where otherwise noted, this item's licence is described as © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/