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  • Review Article
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Maintaining differentiated cellular identity

Nature Reviews Genetics volume 13, pages 429–439 (2012)Cite this article

Subjects

Key Points

  • Reprogramming studies have shown that somatic differentiated cells retain plasticity, but how their identities are stably maintained under normal conditions is not well-understood.

  • Cell fusion experiments have indicated that differentiated cell identity is maintained by continuously expressed instructive regulators.

  • Expression of transcription factors in combination can lead to lineage conversions without passage via immature progenitor states.

  • Differentiated cell identity may be propagated by a simple transcription factor regulatory logic in lower animals and by more complex combinatorial coding in higher animal cells.

  • Conditional gene targeting of key developmental transcription factors in mature cells can, in some cases, lead to dramatic cell lineage switching. Several other examples reveal relatively minor phenotypes.

  • The stability of intrinsic transcription factor networks may contribute to the stability of the differentiated state.

  • Additional mechanisms, including stable and persistent silencing of alternative cell lineages, may also contribute to the stability of the differentiated cell identity.

  • Differences in stability of differentiated cells may reflect different physiological requirements to retain plasticity in some, but not all, types of mature cells.

  • Interference with transcription factor mechanisms that are involved in maintaining cell identity may be associated with diseases such as cancer.

Abstract

Various studies have demonstrated that somatic differentiated cells can be reprogrammed into other differentiated states or into pluripotency, thus showing that the differentiated cellular state is not irreversible. These findings have generated intense interest in the process of reprogramming and in mechanisms that govern the pluripotent state. However, the realization that differentiated cells can be triggered to switch to considerably different lineages also emphasizes that we need to understand how the identity of mature cells is normally maintained. Here we review recent studies on how the differentiated state is controlled at the transcriptional level and discuss how new insights have begun to elucidate mechanisms underlying the stable maintenance of mature cell identities.

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Figure 1: Feedforward regulatory cascades of transcription factors functioning in cell development and maintenance.
Figure 2: Guardians of differentiated cell identities.
Figure 3: Models for how transcription factor networks might control the stability of the differentiated state.
Figure 4: Dependency of instructive factors in the regulation of the chromatin state is distinct for active versus repressed genes.

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Acknowledgements

We would like to thank Ö. Wrange and members of our laboratories for valuable ideas and discussion. This work was supported by grants from the Swedish Research Council via Linnaeus grant (T.P.), the Swedish Strategic Research Foundation (T.P.), the Swedish Research Council (J.H.) and the Swedish Cancer Society (J.H). We apologize to the authors of the many interesting studies that could not be included owing to space constraints.

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  1. Ludwig Institute for Cancer Research Ltd, BOX 240, Karolinska Institutet, Stockholm, S-171 77, Sweden

    Johan Holmberg & Thomas Perlmann

  2. Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, Stockholm, 171 77, Sweden

    Johan Holmberg & Thomas Perlmann

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  1. Johan Holmberg
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Glossary

Somatic cell nuclear transfer

(SCNT). The process by which the nucleus from an adult cell is transferred into a previously enucleated cell; the reconstructed oocyte is activated, which initiates subsequent development.

Reprogramming

The conversion of a differentiated cell to another cell type, either to another differentiated cell type (transdifferentiation) or to a progenitor (dedifferentiation).

Induced pluripotent stem cells

(iPSCs). Pluripotent cells that can be generated from many different types of somatic cells by expression of only a few pluripotency-related transcription factors and that have properties of embryonic stem cells.

Metaplasias

Environmentally induced processes in which one differentiated cell type is transformed into another differentiated cell type.

Heterokaryons

Non-dividing cells that contain two or more nuclei in a common cytoplasm as a consequence of cell fusion between cells of different identities.

Binary cell specification

The process through which two different cell types are specified from a common progenitor.

Feedforward cascades

Hierarchical organization of several transcription factors emanating from an initiating transcription factor that sequentially activates downstream transcription factors that in turn activate each other.

Terminal selectors

Transcription factors that directly control effector genes for determining mature cell identity. They typically act by binding conserved sequence motifs in multiple effector genes, such as in ion channel genes and other neuron-specific genes in neurons. They were first proposed by Hobert for Caenorhabditis elegans neurons but are potentially applicable to other mature cell types.

Effector genes

Genes that define the cell-type-specific functional properties of a terminally differentiated cell.

Epigenetic modifications

Heritable changes in gene expression that do not depend on a change in DNA sequence.

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Holmberg, J., Perlmann, T. Maintaining differentiated cellular identity. Nat Rev Genet 13, 429–439 (2012). https://doi.org/10.1038/nrg3209

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