Primate-specific ZNF808 is essential for pancreatic development in humans
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:55 |
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| Enthalten in: |
Nature genetics - 55(2023), 12 vom: 17. Dez., Seite 2075-2081 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
DNA Transposable Elements |
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| Anmerkungen: |
Date Completed 09.01.2024 Date Revised 09.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41588-023-01565-x |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364655135 |
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| 245 | 1 | 0 | |a Primate-specific ZNF808 is essential for pancreatic development in humans |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
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| 650 | 7 | |a ZNF808 protein, human |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 700 | 1 | |a Owens, Nick D L |e verfasserin |4 aut | |
| 700 | 1 | |a Montaser, Hossam |e verfasserin |4 aut | |
| 700 | 1 | |a Wakeling, Matthew N |e verfasserin |4 aut | |
| 700 | 1 | |a Saarimäki-Vire, Jonna |e verfasserin |4 aut | |
| 700 | 1 | |a Triantou, Athina |e verfasserin |4 aut | |
| 700 | 1 | |a Ibrahim, Hazem |e verfasserin |4 aut | |
| 700 | 1 | |a Balboa, Diego |e verfasserin |4 aut | |
| 700 | 1 | |a Caswell, Richard C |e verfasserin |4 aut | |
| 700 | 1 | |a Jennings, Rachel E |e verfasserin |4 aut | |
| 700 | 1 | |a Kvist, Jouni A |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Matthew B |e verfasserin |4 aut | |
| 700 | 1 | |a Muralidharan, Sachin |e verfasserin |4 aut | |
| 700 | 1 | |a Ellard, Sian |e verfasserin |4 aut | |
| 700 | 1 | |a Wright, Caroline F |e verfasserin |4 aut | |
| 700 | 1 | |a Maddirevula, Sateesh |e verfasserin |4 aut | |
| 700 | 1 | |a Alkuraya, Fowzan S |e verfasserin |4 aut | |
| 700 | 0 | |a Pancreatic Agenesis Gene Discovery Consortium |e verfasserin |4 aut | |
| 700 | 1 | |a Hanley, Neil A |e verfasserin |4 aut | |
| 700 | 1 | |a Flanagan, Sarah E |e verfasserin |4 aut | |
| 700 | 1 | |a Otonkoski, Timo |e verfasserin |4 aut | |
| 700 | 1 | |a Hattersley, Andrew T |e verfasserin |4 aut | |
| 700 | 1 | |a Imbeault, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Laimon, Wafaa |e investigator |4 oth | |
| 700 | 1 | |a Hassan, Samar S |e investigator |4 oth | |
| 700 | 1 | |a Abdullah, Mohamed A |e investigator |4 oth | |
| 700 | 1 | |a Fritzberg, Anders |e investigator |4 oth | |
| 700 | 1 | |a Wakeling, Emma |e investigator |4 oth | |
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| 700 | 1 | |a Elbarbary, Nancy |e investigator |4 oth | |
| 700 | 1 | |a Osman, Amani |e investigator |4 oth | |
| 700 | 1 | |a Alkandari, Hessa |e investigator |4 oth | |
| 700 | 1 | |a alTararwa, Abeer |e investigator |4 oth | |
| 700 | 1 | |a Habeb, Abdelhadi |e investigator |4 oth | |
| 700 | 1 | |a Al-Agha, Abdulmoein Eid |e investigator |4 oth | |
| 700 | 1 | |a Ahmad, Ihab Abdulhamed |e investigator |4 oth | |
| 700 | 1 | |a Aldulaimi, Majida Noori Nasaif |e investigator |4 oth | |
| 700 | 1 | |a Ustyol, Ala |e investigator |4 oth | |
| 700 | 1 | |a Binomar, Hiba Mohammed Amin |e investigator |4 oth | |
| 700 | 1 | |a Shagrani, Mohammad |e investigator |4 oth | |
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