Primate-specific ZNF808 is essential for pancreatic development in humans
In: 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), 2024, S. 2075
Online
academicJournal
Zugriff:
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.Loss-of-function mutations in primate-specific ZNF808 cause pancreatic agenesis. Mechanistically, the loss of ZNF808 leads to the activation of the MER11 family of transposable elements in a regulatory capacity that ultimately induces a liver-specific program of gene expression during pancreatic differentiation. ; Peer reviewed
| Titel: |
Primate-specific ZNF808 is essential for pancreatic development in humans
|
|---|---|
| Autor/in / Beteiligte Person: | Pancreatic Agenesis Gene Discovery ; De Franco, Elisa ; Owens, Nick D. L. ; Montaser, Hossam ; Wakeling, Matthew N. ; Saarimäki-Vire, Jonna ; Triantou, Athina ; Ibrahim, Hazem ; Balboa, Diego ; Caswell, Richard C. ; Jennings, Rachel E. ; Kvist, Jouni A. ; Johnson, Matthew B. ; Muralidharan, Sachin ; Ellard, Sian ; Wright, Caroline F. ; Maddirevula, Sateesh ; Alkuraya, Fowzan S. ; Hanley, Neil A. ; Flanagan, Sarah E. ; Otonkoski, Timo ; Hattersley, Andrew T. ; Imbeault, Michael ; STEMM - Stem Cells and Metabolism Research Program ; Research Programs Unit ; Centre of Excellence in Stem Cell Metabolism ; Helsinki One Health (HOH) ; HUS Children and Adolescents ; Clinicum ; Timo Pyry Juhani Otonkoski / Principal Investigator ; Hospital, Children's |
| Link: | |
| Zeitschrift: | 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), 2024, S. 2075 |
| Veröffentlichung: | Nature Publishing Group, 2024 |
| Medientyp: | academicJournal |
| DOI: | 10.1038/s41588-023-01565-x |
| Schlagwort: |
|
| Sonstiges: |
|