Nature genetics · 2023
Primate-specific ZNF808 is essential for pancreatic development in humans.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, Pancreatic Agenesis Gene Discovery Consortium, Hanley Neil A, Flanagan Sarah E, Otonkoski Timo, Hattersley Andrew T, Imbeault Michael
Аннотация
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.