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Ground rules of the pluripotency gene regulatory network

Nature Reviews Genetics volume 18, pages 180–191 (2017)Cite this article

Subjects

Key Points

  • Pluripotency exists transiently in the early embryo and can be recapitulated in vitro.

  • Pluripotency is stabilized by an interconnected network of pluripotency-associated genes.

  • The pluripotency gene regulatory network integrates external signals, and exerts control over the decision between self-renewal and differentiation at the transcriptional, post-transcriptional and epigenetic levels.

  • Diverse pathways — including chromatin-mediated mechanisms, RNA-based regulation and 3D genome organization — work together to maintain pluripotency.

  • Recent evidence of alternative pluripotency states indicates the regulatory flexibility of this network.

Abstract

Pluripotency is a state that exists transiently in the early embryo and, remarkably, can be recapitulated in vitro by deriving embryonic stem cells or by reprogramming somatic cells to become induced pluripotent stem cells. The state of pluripotency, which is stabilized by an interconnected network of pluripotency-associated genes, integrates external signals and exerts control over the decision between self-renewal and differentiation at the transcriptional, post-transcriptional and epigenetic levels. Recent evidence of alternative pluripotency states indicates the regulatory flexibility of this network. Insights into the underlying principles of the pluripotency network may provide unprecedented opportunities for studying development and for regenerative medicine.

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Figure 1: Bistability of the pluripotency gene regulatory network.
Figure 2: Cooperative binding of pluripotency factors.
Figure 3: Global retargeting of OCT4–SOX2–NANOG binding and remodelling of the enhancer landscape during the transition between pluripotency states.
Figure 4: An RNA-mediated 'tug of war' in the regulation of the pluripotency gene regulatory network.

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Acknowledgements

The authors apologize to the colleagues whose work is not covered in this article because of space constraints. The authors would like to thank D. O'Keefe and M. Schwarz for critical reading and generous help during the preparation of the manuscript. Work in the laboratory of J.C.I.B. is supported by the G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (grant 2012-PG-MED002), the Moxie Foundation, Fundacion Dr. Pedro Guillen and the Universidad Católica San Antonio de Murcia (UCAM).

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Authors and Affiliations

  1. Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Mo Li & Juan Carlos Izpisua Belmonte

  2. Universidad Católica San Antonio de Murcia (UCAM), Campus de los Jerónimos, No. 135, Murcia, 30107, Guadalupe, Spain

    Mo Li

  3. Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, 23955-6900, Thuwal, Saudi Arabia

    Mo Li

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  1. Mo Li
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Correspondence to Juan Carlos Izpisua Belmonte.

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Glossary

Inner cell mass

(ICM). A small cluster of cells inside the early embryo (that is, the blastocyst). These cells give rise to all the tissues of the future embryo but not to extra-embryonic tissues (for example, the placenta). The ICM may be isolated to generate embryonic stem cells.

Trophectoderm

The outer cell layer of a blastocyst. It is formed from the first specialized lineage of cells and gives rise to extra-embryonic tissues.

Mesendoderm

A layer of cells that are formed during early gastrulation, and are destined to become mesoderm and endoderm.

Ectoderm

The outermost of the three germ layers that are formed during gastrulation of the early embryo. Ectoderm-derived tissues include the nervous system, sensory organs and the skin.

Stemness genes

Genes that constitute the stem cell-specific gene expression programme.

Epithelial–mesenchymal transition

(EMT). A process in which cells of an epithelial layer lose their polarity and cell–cell adhesion, and become disorganized migratory mesenchymal cells. EMT is an integral part of normal developmental, wound healing and cancer development.

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Li, M., Belmonte, J. Ground rules of the pluripotency gene regulatory network. Nat Rev Genet 18, 180–191 (2017). https://doi.org/10.1038/nrg.2016.156

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