Genome editing reveals a role for OCT4 in human embryogenesis

Norah M. E. Fogarty, Afshan McCarthy, Kirsten E. Snijders, Benjamin E. Powell, Nada Kubikova, Paul Blakeley, Rebecca Lea, Kay Elder, Sissy E. Wamaitha, Daesik Kim, Valdone Maciulyte, Jens Kleinjung, Jin-Soo Kim, Dagan Wells, Ludovic Vallier, Alessandro Bertero, James M. A. Turner and Kathy K. Niakan ()
Additional contact information
Norah M. E. Fogarty: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute
Afshan McCarthy: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute
Kirsten E. Snijders: NIHR Cambridge Biomedical Research Centre hIPSC Core Facility, University of Cambridge, Cambridge Biomedical Campus
Benjamin E. Powell: Sex Chromosome Biology Laboratory, The Francis Crick Institute
Nada Kubikova: University of Oxford, John Radcliffe Hospital
Paul Blakeley: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute
Rebecca Lea: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute
Kay Elder: Bourn Hall Clinic
Sissy E. Wamaitha: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute
Daesik Kim: Seoul National University
Valdone Maciulyte: Sex Chromosome Biology Laboratory, The Francis Crick Institute
Jens Kleinjung: Bioinformatics Facility, The Francis Crick Institute
Jin-Soo Kim: Seoul National University
Dagan Wells: University of Oxford, John Radcliffe Hospital
Ludovic Vallier: NIHR Cambridge Biomedical Research Centre hIPSC Core Facility, University of Cambridge, Cambridge Biomedical Campus
Alessandro Bertero: Wellcome Trust and MRC Cambridge Stem Cell Institute and Biomedical Research Centre, Anne McLaren Laboratory, University of Cambridge
James M. A. Turner: Sex Chromosome Biology Laboratory, The Francis Crick Institute
Kathy K. Niakan: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute

Nature, 2017, vol. 550, issue 7674, 67-73

Abstract: Abstract Despite their fundamental biological and clinical importance, the molecular mechanisms that regulate the first cell fate decisions in the human embryo are not well understood. Here we use CRISPR–Cas9-mediated genome editing to investigate the function of the pluripotency transcription factor OCT4 during human embryogenesis. We identified an efficient OCT4-targeting guide RNA using an inducible human embryonic stem cell-based system and microinjection of mouse zygotes. Using these refined methods, we efficiently and specifically targeted the gene encoding OCT4 (POU5F1) in diploid human zygotes and found that blastocyst development was compromised. Transcriptomics analysis revealed that, in POU5F1-null cells, gene expression was downregulated not only for extra-embryonic trophectoderm genes, such as CDX2, but also for regulators of the pluripotent epiblast, including NANOG. By contrast, Pou5f1-null mouse embryos maintained the expression of orthologous genes, and blastocyst development was established, but maintenance was compromised. We conclude that CRISPR–Cas9-mediated genome editing is a powerful method for investigating gene function in the context of human development.

Date: 2017
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DOI: 10.1038/nature24033

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