Primate-specific ZNF808 is essential for pancreatic development in humans

Author:

De Franco ElisaORCID,Owens Nick D. L.ORCID,Montaser Hossam,Wakeling Matthew N.ORCID,Saarimäki-Vire Jonna,Triantou Athina,Ibrahim HazemORCID,Balboa DiegoORCID,Caswell Richard C.ORCID,Jennings Rachel E.,Kvist Jouni A.ORCID,Johnson Matthew B.,Muralidharan Sachin,Ellard Sian,Wright Caroline F.ORCID,Maddirevula Sateesh,Alkuraya Fowzan S.ORCID,Laimon Wafaa,Hassan Samar S.,Abdullah Mohamed A.,Fritzberg Anders,Wakeling Emma,Nathwani Nisha,Elbarbary Nancy,Osman Amani,Alkandari Hessa,alTararwa Abeer,Habeb Abdelhadi,Al-Agha Abdulmoein Eid,Ahmad Ihab Abdulhamed,Aldulaimi Majida Noori Nasaif,Ustyol Ala,Binomar Hiba Mohammed Amin,Shagrani Mohammad,Hanley Neil A.ORCID,Flanagan Sarah E.ORCID,Otonkoski TimoORCID,Hattersley Andrew T.ORCID,Imbeault MichaelORCID,

Abstract

AbstractIdentifying 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.

Funder

Wellcome Trust

Diabetes UK

European Foundation for the Study of Diabetes

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

Doctoral Program in Integrative Life Science at University of Helsinki

Foundation for Education and European Culture

Gates Cambridge Trust

European Molecular Biology Organization

King Salman Center for Disability Research

RCUK | Medical Research Council

Academy of Finland

Novo Nordisk Fonden

Sigrid Juséliuksen Säätiö

Publisher

Springer Science and Business Media LLC

Subject

Genetics

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