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Mediators of reprogramming: transcription factors and transitions through mitosis

Key Points

  • The genome remains mostly constant during development and ageing.

  • Cells differ in which part of the genome they express. The gene-expression programme is determined by the presence of transcriptional regulators.

  • The cloning of various organisms from different cell types shows that the differentiated state and cellular changes that occur during ageing are reversible. This reversion is referred to as reprogramming.

  • Transcriptional regulators dissociate from the chromatin during cell division. The transcriptional programme, and with it a cellular state, is newly established after every cell division, thereby challenging the old state as well as providing the opportunity to transit to another state.

  • Exposing a genome to a different set of transcriptional regulators can change its gene-expression programme and with it cellular identity. This can be done by ectopic expression of transcription factors, cell fusion or nuclear transfer.

  • Transfer of a somatic cell genome into an unfertilized oocyte or a zygote in mitosis allows the derivation of pluripotent embryonic stem-cell lines from the cloned preimplantation stage embryos.

  • Fusion of a somatic cell with an embryonic stem cell can reprogramme the somatic cell genome to an embryonic state.

  • The ectopic expression of a combination of embryonic stem-cell transcription factors can reprogramme a somatic cell to an embryonic state.

Abstract

It is thought that most cell types of the human body share the same genetic information as that contained in the zygote from which they originate. Consistent with this view, animal cloning studies demonstrated that the intact genome of a differentiated cell can be reprogrammed to support the development of an entire organism and allow the production of pluripotent stem cells. Recent progress in reprogramming research now points to an important role for transcription factors in the establishment and the maintenance of cellular phenotypes, and to cell division as a mediator of transitions between different states of gene expression.

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Figure 1: Cell-cycle synchronization after nuclear transfer.
Figure 2: Genome exchange during cell division allows development of clones.
Figure 3: Regulators of gene expression dissociate from mitotic chromatin.
Figure 4: Model of reprogramming after transfer of a somatic cell genome into an oocyte or zygote in cell division.
Figure 5: Different methods of reprogramming require transcriptional regulators and passage through cell division.

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Acknowledgements

D.E. thanks I. Tabansky, A. J. Tanaka, C. Fitzgerald, A. Chen, K. Rodolfa, R. Jiao, K. Niakan, S. Sullivan, A. Tajonar, E. Son and R. Maehr for comments on the manuscript. D.E. is supported by a Harvard Stem Cell Institute (USA) seed grant funded by the Singer family foundation. K.E. is a fellow of the John D. and Catherine T. MacArthur Foundation. We apologize for the many exciting studies that could not be included in this article because of space constraints.

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Supplementary information

41580_2008_BFnrm2439_MOESM1_ESM.pdf

Supplementary information S1 (table) | Factors with nuclear localization during interphase and dissociation from chromatin during mitosis or meiosis (PDF 246 kb)

Supplementary information S2 (table) | Factors that tend to be associated with chromatin during mitosis (PDF 189 kb)

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Glossary

Nuclear transfer

(NT). The transfer of a genome within an intact nucleus during interphase.

Terminally differentiated cell

A cell that does not give rise to a cell type other than that of itself.

Oocyte

An unfertilized egg.

Reprogramming

An induced transition in cellular identity, usually meaning the reversal of differentiation.

Cellular state

A cellular phenotype that includes developmental potential, the state of differentiation and functional specialization, replicative life-span and whether a cell is transformed to display aspects of disease.

Zygote

A fertilized egg.

Blastocyst

The embryo before implantation that contains at least two distinct cell types: the trophectoderm and the inner cell mass.

Chromosome transfer

The transfer of a genome that is packaged in condensed chromosomes.

Replication origin

A site where replication is initiated during S phase. It is bound by the origin of replication complex.

M phase

Mitosis and meiosis.

Topoisomerase II

(topo II). A protein that decatenates DNA in an ATP-dependent manner. It is also required for chromosome condensation.

Cytoplast

A cell that does not contain a nuclear genome, but does contain mitochondria with genetic information.

Embryonic stem cell

(ES). A pluripotent cell that can be derived from the inner cell mass of the blastocyst-stage embryo.

Homeotic genes

Genes that encode homeodomain-containing transcription factors that are involved in the patterning of the body during development.

Heterochromatin

DNA packed into a transcriptionally repressive chromatin structure.

Pericentric heterochromatin

The heterochromatin of the chromosomal arms that is close to the centromeres.

Euchromatin

A form of chromatin that is lightly packed and often transcriptionally active during interphase.

Karyoplast

A nucleus or mitotic genome without the cytoplasm.

Pluripotent stem cell

A cell that can give rise to cell types of the three germ layers — endoderm, mesoderm and ectoderm — and to germ cells.

Cell fusion

The fusion of two or more cells resulting in a single, fused cell. This can be done by the application of an electric field or chemicals, such as polyethylene glycol.

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Egli, D., Birkhoff, G. & Eggan, K. Mediators of reprogramming: transcription factors and transitions through mitosis. Nat Rev Mol Cell Biol 9, 505–516 (2008). https://doi.org/10.1038/nrm2439

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