Background: NANOG function examined directly in human embryos

A study reports that loss of NANOG function in human embryos impairs specification of the pluripotent epiblast and shifts cells toward transcriptional programs associated with other early lineages. Published in Nature, the study investigated NANOG in human embryos using ABE8e adenine base editing.

How the first cell lineages are specified and maintained in early development is a foundational question for regenerative medicine and research into infertility and pregnancy loss. Studies in mice have helped explain the transcription factors that regulate early development. Applying those findings to human embryos, however, requires consideration of ethical and technical constraints as well as biological differences.

Tools for directly studying transcription factor function in human embryos have also been limited. Nuclease-based genome editing, which cuts DNA, can cause genotoxicity. The researchers chose base editing as an approach intended to reduce this constraint.

Key findings: NANOG loss altered early cell lineages

The researchers used ABE8e to precisely target an exon splice-donor site in the NANOG gene. Editing a site involved in RNA splicing caused a splicing defect and induced a functional knockout that eliminated NANOG function.

In human embryos lacking NANOG, specification of the pluripotent epiblast was impaired. Instead, cells adopted transcriptional programs associated with primitive endoderm, which is related to the yolk-sac lineage, or trophectoderm, which is related to the placental lineage. The central finding is a shift in gene-expression patterns characteristic of these cell lineages. It does not demonstrate the formation of a mature yolk sac or placenta.

Primitive endoderm differentiation was maintained in the NANOG-edited human embryos. The researchers interpreted this as functional compensation that distinguishes humans from mice. The result supports investigating function directly in human embryos to understand early human development. The abstract, however, does not identify the factor or molecular pathway responsible for this compensation.

The study also reported findings about the editing approach. According to the researchers, the experiments did not induce genotoxicity, and off-target editing was limited. These results apply to the conditions tested; they do not establish safety under all conditions or the complete absence of off-target editing.

Significance and outlook: Accounting for differences across species

The study provides functional evidence in human embryos that NANOG is essential for pluripotency and epiblast specification. In particular, the persistence of primitive endoderm differentiation after NANOG function was lost shows why findings about transcription factor function in mice cannot necessarily be applied directly to humans. The regulatory relationships underlying this compensation remain a subject for future research.

Base editing is also attracting attention as a tool for investigating regulators of early human development. In this study, the researchers targeted a specific splicing site, eliminated NANOG function, and examined changes in cell lineages. This approach may be useful for directly testing the roles of developmental regulators.

The available evidence is limited to the bibliographic information and abstract. The materials provided do not specify the number of embryos, editing efficiency, magnitude of lineage-specific changes, observation period, or detailed analytical methods, making it difficult to assess the quantitative strength of the findings or their long-term effects. This was not a clinical study testing the effectiveness of infertility treatments or improvements in cell-therapy production.

The methods and main findings are described in the paper abstract indexed in Europe PMC.