Stem cells, including pluripotent embryonic stem (ES) cells and lineage-restricted adult stem cells, share a capacity to self-renew and generate differentiated progeny. Analysis of their epigenetic properties can help us to understand the molecular mechanism that underlies this important property.
Data from different approaches, including fluorescent recovery after photobleaching (FRAP) and replication timing analysis, have suggested that the chromatin of ES cells is generally less compact and more 'permissive' than that of normal cells.
Promoters of many non-transcribed developmental regulator genes share an unusual 'bivalent' chromatin pattern in ES cells, whereby histone modifications that are normally associated with gene transcription (acetylation at lysine 9 and trimethylation at lysine 4 of histone H3) co-exist with trimethylation at lysine 27 of histone H3, which is usually found at repressed loci.
These bivalent patterns are thought to keep non-transcribed genes in a 'poised' conformation, ready for expression in response to developmental cues.
Trimethylation of histone H3 lysine 27 is created by Polycomb repressive complex 2 (PRC2), which in turn provides a binding site for PRC1. Consistently, ES cells that are mutant for Polycomb components show derepression of several tissue-specific genes that carry bivalent chromatin marks in wild-type cells.
Polycomb complexes are ubiquitously expressed, whereas bivalent chromatin is unusual and is not thought to be commonly found in differentiated cells.
Genome-wide studies indicate that Polycomb target genes in ES cells are often co-occupied by a 'triad' of pluripotency-associated transcription factors: OCT4, SOX2 and NANOG. This suggests that these factors might have a role in recruiting Polycomb complexes to target promoters, possibly along with chromatin modifiers with an opposing function (such as histone acetyltransferases). However, many Polycomb targets in ES cells do not bind the regulatory 'triad', indicating that our knowledge of these events remains preliminary.
Polycomb complexes are also important for the maintenance of adult stem-cell populations. Whether they create bivalent chromatin in this context remains to be found.
Pluripotent stem cells, similar to more restricted stem cells, are able to both self-renew and generate differentiated progeny. Although this dual functionality has been much studied, the search for molecular signatures of 'stemness' and pluripotency is only now beginning to gather momentum. While the focus of much of this work has been on the transcriptional features of embryonic stem cells, recent studies have indicated the importance of unique epigenetic profiles that keep key developmental genes 'poised' in a repressed but activatable state. Determining how these epigenetic features relate to the transcriptional signatures of ES cells, and whether they are also important in other types of stem cell, is a key challenge for the future.
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M.S. and A.G.F. thank the Medical Research Council UK for continued support.
The authors declare no competing financial interests.
Describes cells that can, in theory, differentiate into every cell type of the adult organism.
- Lineage restriction
The narrowing down of a range of differentiation pathways that a cell is able to follow.
- Polycomb group proteins
A group of transcriptional repressors that are required to maintain the inactive state of genes during development. Polycomb proteins are known to modify the chromatin structure around their binding sites, which include the promoters of many developmental regulator genes.
- Inner cell mass
A small clump of apparently undifferentiated cells in the blastocyst, which gives rise to the entire fetus and some of its extraembryonic membranes.
An early stage of mammalian embryonic development at which the first cell lineages become established.
- Primordial germ layer
An embryonic layer that will give rise to gametes in the adult organism.
- DNA methylation
An epigenetically propagated covalent modification of DNA that, in mammals, occurs at cytosine deoxynucleotides. DNA methylation is thought to inhibit transcription, both by preventing transcription-factor binding to DNA and through interactions with methyl-CpG-binding proteins that recruit histone-modifying and chromatin-remodelling factors.
- Small interfering RNAs
(siRNAs). Small antisense RNAs (20–25 nucleotides long) that are generated from specific dsRNAs. siRNAs trigger RNAi pathways, which negatively regulate gene expression by post-transcriptional mechanisms.
- Constitutive heterochromatin
Areas of inactive chromatin that remain condensed in all tissue types. It is usually found at chromosomal regions that contain a high density of repetitive DNA elements, such as centromeres and telomeres.
- Fluorescent recovery after photobleaching
A microscopy-based technique that is used to measure the movement (for example, diffusion rates) of fluorescently tagged molecules (usually proteins) over time in vivo. Specific regions in a cell are irreversibly photobleached using a laser. Over time, fluorescence is usually restored as unbleached molecules diffuse into the bleached area. The recovery time can be used as a measure of protein mobility.
- Embryonic carcinoma cells
Cell lines that are derived from tumours that arise from transplantation of early-stage embryos to immunologically compatible animals. These cells can differentiate into many tissue types, and studies using them have pioneered stem-cell research. However, embryonic carcinoma cells have a significantly more restricted lineage potential than ES cells and show a high degree of variation depending on a cell line.
- Carrier ChIP
A chromatin immunoprecipitation technique that uses carrier DNA to allow small amounts of starting material to be analysed.
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Spivakov, M., Fisher, A. Epigenetic signatures of stem-cell identity. Nat Rev Genet 8, 263–271 (2007). https://doi.org/10.1038/nrg2046
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