Primate-specific ZNF808 is essential for pancreatic development in humans

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

doi:10.1038/s41588-023-01565-x

Primate-specific ZNF808 is essential for pancreatic development in humans

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

Dasman Diabetes Institute

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2075-2081
Number of pages	7
Journal	Nature Genetics
Volume	55
Issue number	12
DOIs	https://doi.org/10.1038/s41588-023-01565-x
State	Published - Dec 2023

Funding Agency

Kuwait Foundation for the Advancement of Sciences

Access to Document

10.1038/s41588-023-01565-x

Cite this

De Franco, E., Owens, N. D. L., Montaser, H., Wakeling, M. N., Saarimäki-Vire, J., Triantou, A., Ibrahim, H., Balboa, D., Caswell, R. C., Jennings, R. E., Kvist, J. A., Johnson, M. B., Muralidharan, S., Ellard, S., Wright, C. F., Maddirevula, S., Alkuraya, F. S., Laimon, W., Hassan, S. S., ... Imbeault, M. (2023). Primate-specific ZNF808 is essential for pancreatic development in humans. Nature Genetics, 55(12), 2075-2081. https://doi.org/10.1038/s41588-023-01565-x

@article{04c2e739703546e38483564c65944e34,

title = "Primate-specific ZNF808 is essential for pancreatic development in humans",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41588-023-01565-x",

language = "English",

volume = "55",

pages = "2075--2081",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

De Franco, E, Owens, NDL, Montaser, H, Wakeling, MN, Saarimäki-Vire, J, Triantou, A, Ibrahim, H, Balboa, D, Caswell, RC, Jennings, RE, Kvist, JA, Johnson, MB, Muralidharan, S, Ellard, S, Wright, CF, Maddirevula, S, Alkuraya, FS, Laimon, W, Hassan, SS, Abdullah, MA, Fritzberg, A, Wakeling, E, Nathwani, N, Elbarbary, N, Osman, A, Alkandari, H, alTararwa, A, Habeb, A, Al-Agha, AE, Ahmad, IA, Aldulaimi, MNN, Ustyol, A, Binomar, HMA, Shagrani, M, Hanley, NA, Flanagan, SE, Otonkoski, T, Hattersley, AT & Imbeault, M 2023, 'Primate-specific ZNF808 is essential for pancreatic development in humans', Nature Genetics, vol. 55, no. 12, pp. 2075-2081. https://doi.org/10.1038/s41588-023-01565-x

TY - JOUR

T1 - Primate-specific ZNF808 is essential for pancreatic development in humans

AU - De Franco, Elisa

AU - Owens, Nick D.L.

AU - Montaser, Hossam

AU - Wakeling, Matthew N.

AU - Saarimäki-Vire, Jonna

AU - Triantou, Athina

AU - Ibrahim, Hazem

AU - Balboa, Diego

AU - Caswell, Richard C.

AU - Jennings, Rachel E.

AU - Kvist, Jouni A.

AU - Johnson, Matthew B.

AU - Muralidharan, Sachin

AU - Ellard, Sian

AU - Wright, Caroline F.

AU - Maddirevula, Sateesh

AU - Alkuraya, Fowzan S.

AU - Laimon, Wafaa

AU - Hassan, Samar S.

AU - Abdullah, Mohamed A.

AU - Fritzberg, Anders

AU - Wakeling, Emma

AU - Nathwani, Nisha

AU - Elbarbary, Nancy

AU - Osman, Amani

AU - Alkandari, Hessa

AU - alTararwa, Abeer

AU - Habeb, Abdelhadi

AU - Al-Agha, Abdulmoein Eid

AU - Ahmad, Ihab Abdulhamed

AU - Aldulaimi, Majida Noori Nasaif

AU - Ustyol, Ala

AU - Binomar, Hiba Mohammed Amin

AU - Shagrani, Mohammad

AU - Hanley, Neil A.

AU - Flanagan, Sarah E.

AU - Otonkoski, Timo

AU - Hattersley, Andrew T.

AU - Imbeault, Michael

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85176724064&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01565-x

DO - 10.1038/s41588-023-01565-x

M3 - Article

C2 - 37973953

AN - SCOPUS:85176724064

SN - 1061-4036

VL - 55

SP - 2075

EP - 2081

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Primate-specific ZNF808 is essential for pancreatic development in humans

Abstract

Funding Agency

Access to Document

Other files and links

Fingerprint

Cite this