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Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal

Key Points

  • The life cycle of an organism is characterized by phases of reprogramming and differentiation during development from the zygote to the adult organism.

  • Epigenetic reprogramming occurs in primordial germ cells (PGCs) and in the early embryo. Reprogramming is an essential characteristic of the immortality of the germ line in which epigenetic imprints are erased and reset in a parent-of-origin-dependent manner. Epigenetic reprogramming in PGCs and on fertilization is required to restore totipotency in the early embryo and perhaps to erase epimutations.

  • Cells of the early mammalian embryo as well as pluripotent embryonic stem (ES) cells and PGCs are epigenetically dynamic and heterogeneous. During early development, this heterogeneity of epigenetic states is associated with stochastic expression of lineage-determining transcription factors that establish an intimate crosstalk with epigenetic modifiers.

  • Subsequent development is characterized by the progressive restriction of cellular plasticity that is accompanied by the gradual acquisition of epigenetic marks. This epigenetic programming is important for cell differentiation and the specification of the principal cell lineages of the early conceptus.

  • Once the lineages have been specified, DNA methylation of a few crucial loci, notably Elf5 and possibly also Stella (also known as Dppa3), is required to restrict their differentiation potential and to establish lineage-committed cell populations, the fate allocation of which is stably inherited by all descendants.

  • Reversion of developmental progression to generate induced pluripotent stem (iPS) cells that are functionally similar to ES cells can be achieved experimentally by temporal overexpression of a few pluripotency factors, namely OCT4 (encoded by Pou5f1), SRY box-containing factor 2 (SOX2), kruppel-like factor 4 (KLF4) and MYC. iPS cell derivation requires marked epigenetic reprogramming of the parent cell, and its efficiency can be enhanced by inhibitors of epigenetic modifiers.

Abstract

Cells of the early mammalian embryo, including pluripotent embryonic stem (ES) cells and primordial germ cells (PGCs), are epigenetically dynamic and heterogeneous. During early development, this heterogeneity of epigenetic states is associated with stochastic expression of lineage-determining transcription factors that establish an intimate crosstalk with epigenetic modifiers. Lineage-specific epigenetic modification of crucial transcription factor loci (for example, methylation of the Elf5 promoter) leads to the restriction of transcriptional circuits and the fixation of lineage fate. The intersection of major epigenetic reprogramming and programming events in the early embryo creates plasticity followed by commitment to the principal cell lineages of the early conceptus.

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Figure 1: Key differentiation stages in development and derived stem cell types.
Figure 2: Epigenetic dynamics in early embryos and germ cells.
Figure 3: Stochasticity of gene expression, developmental potency and lineage commitment.
Figure 4: Crosstalk between pluripotency factors and epigenetic modifiers.
Figure 5: Cellular potency in development and reprogramming.

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Acknowledgements

The authors thank all their colleagues for advice and discussion. Work in the authors' laboratories is supported by the Biotechnology and Biological Sciences Research Council, the Medical Research Council, the European Union Epigenome Network of Excellence, the Technology Strategy Board and CellCentric.

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Correspondence to Myriam Hemberger or Wolf Reik.

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Glossary

Reprogramming

The resetting of epigenetic marks, usually to achieve wider developmental potency. Reprogramming occurs during the life cycle in the early embryo and in the germ line, and also in experimental systems in which differentiated cells are converted into induced pluripotent stem cells.

Totipotency

The differentiative capacity of a cell to form all cell types of the conceptus and the adult organism, including extraembryonic membranes, the placenta and germ cells.

Protamine

A highly basic non-histone protein that replaces histones in the sperm to achieve dense packaging of DNA.

Blastocyst

The embryo before implantation that contains at least two distinct cell types: an outer epithelial cell layer (trophectoderm) and an inner group of cells (inner cell mass).

Egg cylinder

The embryonic stage after implantation that comprises a double-layered structure of the outer endoderm and the inner embryonic or extraembryonic (trophoblast) ectoderm, enclosing a narrow lumen.

Primitive streak

A structure that is formed at the posterior end of amniote embryos at gastrulation stages and is the area of mesoderm formation.

Chromocentre

An aggregate of constitutive heterochromatin comprising pericentric and centric regions from different chromosomes.

Facultative heterochromatin

The fraction of chromatin that is condensed and inactive in a given cell lineage, which can be decondensed and active in another.

Constitutive heterochromatin

The fraction of heterochromatin that stays compact throughout the cell cycle. It is mainly composed of repetitive sequences (satellite DNA) and is concentrated in characteristic regions, such as centromeres.

Pericentromeric heterochromatin

The heterochromatin structure composed mostly of satellite repeats that are located adjacent to the centric satellites. Together these comprise the centromeres and form an important structural element for chromosome stability.

Centromere

The region of a chromosome that is attached to the spindle during nuclear division.

Morula

A ball of cells that is created by the first cleavage divisions, before compaction, that initiates the formation of the blastocyst.

Blastomere

A cell that is generated during the first embryonic cleavage divisions after fertilization.

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Hemberger, M., Dean, W. & Reik, W. Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal. Nat Rev Mol Cell Biol 10, 526–537 (2009). https://doi.org/10.1038/nrm2727

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