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Peer-reviewedCC BY 4.0Nature

Base editing reveals an essential role for NANOG in human embryogenesis

  • Oliver J. Bower1,2
  • Ana Elisa Ribeiro Orsi2
  • Riley McMahon2
  • Desislava P. Staneva2
  • Josephine R. Blagrove2
  • Kashish Singh3
  • Claire S. Simon2
  • Afshan McCarthy1
  • Patricia Garcia4
  • Valerie Shaikly4
  • Mohamed Taranissi4
  • Martin Wilding5
13 more authors
  • Paul F. Serhal6
  • Rabi A. Odia6
  • Mina Vasilic6
  • Meenakshi Choudhary7
  • Athanasios Papathanasiou8
  • Kay T. Elder8
  • Phil Snell8
  • Leila Christie8
  • Mandana Arbab9,10,11,12
  • David R. Liu9,13,11
  • Mary Herbert14,7
  • Katarina Harasimov15,16
  • Kathy K. Niakan17,18,19,20
20 affiliations
  1. 1Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London, UK
  2. 2Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
  3. 3MRC Laboratory of Molecular Biology, Cambridge, UK
  4. 4Assisted Reproduction and Gynaecology Centre, London, UK
  5. 5Create Fertility, London, UK
  6. 6Centre for Reproductive and Genetic Health, London, UK
  7. 7Newcastle Fertility Centre, Newcastle upon Tyne Hospitals NHS Trust, Biosciences Institute, Newcastle University Centre for Life, Newcastle upon Tyne, UK
  8. 8Bourn Hall Clinic, Bourn, UK
  9. 9Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
  10. 10Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
  11. 11Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA
  12. 12Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, USA
  13. 13Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA
  14. 14Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  15. 15Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. [email protected]
  16. 16Sidney Sussex College, Cambridge, UK. [email protected]
  17. 17Epigenetics Programme, Babraham Institute, Cambridge, UK. [email protected]
  18. 18Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London, UK. [email protected]
  19. 19Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. [email protected]
  20. 20Wellcome Trust - Medical Research Council Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. [email protected]
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Abstract

Understanding how the first cell lineages in human development are specified and maintained has fundamental importance and clinical implications for regenerative medicine, infertility and pregnancy loss. Although mouse models have provided valuable insights into transcription factors regulating early development, translating these findings to human embryos has been limited by ethical, technical and biological constraints. Functional studies of transcription factors in human embryos have been hindered by nuclease-based genome editing approaches that induce genotoxicity 1–3 . Here, to overcome this, we applied ABE8e adenine base editing 4,5 to precisely target an exon splice donor site, resulting in a splicing defect and functional knockout of the developmental regulator NANOG in human embryos. This approach did not trigger genotoxicity and showed limited off-target editing. Loss of NANOG disrupts pluripotent epiblast specification and instead cells differentiate towards a primitive endoderm (yolk sac) or trophectoderm (placental) transcriptional programme. Retention of primitive endoderm differentiation in NANOG -edited human embryos reveals a functional compensation that is distinct from mouse, underscoring the importance of directly investigating human development. Our findings demonstrate an essential role for NANOG in human pluripotency and epiblast specification and highlight the utility of base editing for functional interrogation of human development.

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Cite

BibTeXRIS
BibTeX
@article{bower2026base,
  title = {{Base editing reveals an essential role for NANOG in human embryogenesis}},
  author = {Oliver J. Bower and Ana Elisa Ribeiro Orsi and Riley McMahon and Desislava P. Staneva and Josephine R. Blagrove and Kashish Singh and Claire S. Simon and Afshan McCarthy and Patricia Garcia and Valerie Shaikly and Mohamed Taranissi and Martin Wilding and Paul F. Serhal and Rabi A. Odia and Mina Vasilic and Meenakshi Choudhary and Athanasios Papathanasiou and Kay T. Elder and Phil Snell and Leila Christie and Mandana Arbab and David R. Liu and Mary Herbert and Katarina Harasimov and Kathy K. Niakan},
  journal = {Nature},
  year = {2026},
  month = jun,
  doi = {10.1038/s41586-026-10792-1},
  url = {https://doi.org/10.1038/s41586-026-10792-1},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Base editing reveals an essential role for NANOG in human embryogenesis
AU  - Oliver J. Bower
AU  - Ana Elisa Ribeiro Orsi
AU  - Riley McMahon
AU  - Desislava P. Staneva
AU  - Josephine R. Blagrove
AU  - Kashish Singh
AU  - Claire S. Simon
AU  - Afshan McCarthy
AU  - Patricia Garcia
AU  - Valerie Shaikly
AU  - Mohamed Taranissi
AU  - Martin Wilding
AU  - Paul F. Serhal
AU  - Rabi A. Odia
AU  - Mina Vasilic
AU  - Meenakshi Choudhary
AU  - Athanasios Papathanasiou
AU  - Kay T. Elder
AU  - Phil Snell
AU  - Leila Christie
AU  - Mandana Arbab
AU  - David R. Liu
AU  - Mary Herbert
AU  - Katarina Harasimov
AU  - Kathy K. Niakan
PY  - 2026
DA  - 2026/06/25
JO  - Nature
DO  - 10.1038/s41586-026-10792-1
UR  - https://doi.org/10.1038/s41586-026-10792-1
AB  - Understanding how the first cell lineages in human development are specified and maintained has fundamental importance and clinical implications for regenerative medicine, infertility and pregnancy loss. Although mouse models have provided valuable insights into transcription factors regulating early development, translating these findings to human embryos has been limited by ethical, technical and biological constraints. Functional studies of transcription factors in human embryos have been hindered by nuclease-based genome editing approaches that induce genotoxicity 1–3 . Here, to overcome this, we applied ABE8e adenine base editing 4,5 to precisely target an exon splice donor site, resulting in a splicing defect and functional knockout of the developmental regulator NANOG in human embryos. This approach did not trigger genotoxicity and showed limited off-target editing. Loss of NANOG disrupts pluripotent epiblast specification and instead cells differentiate towards a primitive endoderm (yolk sac) or trophectoderm (placental) transcriptional programme. Retention of primitive endoderm differentiation in NANOG -edited human embryos reveals a functional compensation that is distinct from mouse, underscoring the importance of directly investigating human development. Our findings demonstrate an essential role for NANOG in human pluripotency and epiblast specification and highlight the utility of base editing for functional interrogation of human development.
SN  - 0028-0836
SN  - 1476-4687
ER  -