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Primate-specific ZNF808 is essential for pancreatic development in humans.

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Peer-reviewed

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Authors

Montaser, Hossam 
Wakeling, Matthew N  ORCID logo  https://orcid.org/0000-0002-6542-9241
Saarimäki-Vire, Jonna 

Abstract

Identifying genes linked to extreme phenotypes in humans has the potential to highlight 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 family, a large and rapidly evolving group of epigenetic silencers which 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 in pancreatic development in humans and the contribution of primate-specific regions of the human genome to congenital developmental disease.

Description

Acknowledgements: We are grateful to the patients and their families for taking part in our gene discovery study. We also thank S. Eurola, J. Ustinov and R. Ward for expert technical assistance. This work was supported by a Wellcome Trust Collaborative Award in Science to E.D.F., N.D.L.O., T.O., A.T.H. and M.I. (grant no. 224600/Z/21/Z). E.D.F. is a Diabetes UK RD Lawrence Fellow (19/005971) and has been the recipient of an EFSD Rising Star fellowship during this study. A.T.H. and S.E. were the recipients of a Wellcome Trust Senior Investigator award (grant no. WT098395/Z/12/Z) during this study and A.T.H. is employed as a core member of staff in the NIH Research-funded Exeter Clinical Research Facility and is an NIHR Emeritus Senior Investigator. M.I. has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant no. 206688/Z/17/Z). S.E.F. has a Wellcome Trust Senior Research Fellowship (grant no. 105636/Z/14/Z). N.D.L.O. has a lectureship funded by a Research England’s Expanding Excellence in England (E3) award. M.B.J. and M.N.W. are recipients of an Exeter Diabetes Centre of Excellence Independent Fellowship funded by E3. The work was supported by the National Institute for Health Research (NIHR) Exeter Biomedical Research Centre, Exeter, UK. R.E.J. is a Diabetes UK Harry Keen Clinician Scientist fellow (20/0006263) and received an Academy of Sciences Starter grant during this project. N.A.H. is funded by the Medical Research Council (grant nos. MR/000638/1 and MR/S036121/1). Most of the experimental studies were funded by the Academy of Finland Center of Excellence MetaStem (grant no. 312437), the Novo Nordisk Foundation (grant no. 0057286) and the Sigrid Juselius Foundation. H.M. is a member of the Doctoral Program in Integrative Life Science at University of Helsinki. A.T.’s doctoral studies were funded by the Foundation for Education and European Culture (IPEP) in Greece and by the Cambridge Trust. D.B. received funding from a European Molecular Biology Organization long-term fellowship (ALTF 295-2019). King Salman Center for Disability Research funded exome sequencing analysis for one case through Research Group no. RG-2022-010. For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission.


Funder: European Foundation for the Study of Diabetes (EFSD); doi: https://doi.org/10.13039/501100001648


Funder: Research England’s Expanding Excellence in England (E3) fund


Funder: Doctoral Program in Integrative Life Science at University of Helsinki


Funder: Foundation for Education and European Culture (IPEP); doi: https://doi.org/10.13039/501100005411


Funder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370


Funder: King Salman Center for Disability Research


Funder: Sigrid Juséliuksen Säätiö (Sigrid Jusélius Foundation); doi: https://doi.org/10.13039/501100006306

Keywords

Animals, Humans, Cell Differentiation, DNA Transposable Elements, Genome, Human, Primates, DNA-Binding Proteins, Congenital Abnormalities, Pancreas

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

55

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (206688/Z/17/Z)
Wellcome Trust (via University of Exeter) (119958R)