Primate-specific ZNF808 is essential for pancreatic development in humans
Primate-specific ZNF808 is essential for pancreatic development in humans
Summary Identifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes fundamental for human development. 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 many transposable elements it normally represses during early pancreas development. This results in inappropriate specification of cell fate with induction of genes associated with liver endoderm and a loss of pancreatic identity. We show that ZNF808 and its transposable element targets play a critical role in cell fate specification during human pancreatic development. This is the first report of loss of a primate-specific gene causing a congenital developmental disease and highlights the essential role of ZNF808 for pancreatic development in humans.
De Franco Elisa、Owens Nick D L、Wakeling Matthew N、Balboa Diego、Wright Caroline F、Flanagan Sarah E、Imbeault Michael、Otonkoski Timo、Ellard Sian、Triantou Athina、Caswell Richard C、Ibrahim Hazem、Saarim?ki-Vire Jonna、Johnson Matthew B、Hattersley Andrew T、Montaser Hossam、Pancreatic Agenesis Gene Discovery Consortium
Institute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthRegulatory Genomics and Diabetes, Centre for Genomic Regulation, Barcelona Institute of Science and TechnologyInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthDepartment of Genetics. University of CambridgeStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki||Children?ˉs Hospital, Helsinki University Hospital, and University of HelsinkiGenomics Laboratory, Royal Devon and Exeter Foundation TrustDepartment of Genetics. University of CambridgeInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthInstitute of Biomedical and Clinical Sciences, University of Exeter College of Medicine and HealthStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki
基础医学遗传学分子生物学
De Franco Elisa,Owens Nick D L,Wakeling Matthew N,Balboa Diego,Wright Caroline F,Flanagan Sarah E,Imbeault Michael,Otonkoski Timo,Ellard Sian,Triantou Athina,Caswell Richard C,Ibrahim Hazem,Saarim?ki-Vire Jonna,Johnson Matthew B,Hattersley Andrew T,Montaser Hossam,Pancreatic Agenesis Gene Discovery Consortium.Primate-specific ZNF808 is essential for pancreatic development in humans[EB/OL].(2025-03-28)[2025-05-21].https://www.medrxiv.org/content/10.1101/2021.08.23.21262262.点此复制
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