Key Points
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Pluripotent stem cells, such as embryonic stem cells, maintain the capacity to differentiate into all cell types of the body through a complex regulatory mechanism that involves a particular chromatin landscape.
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Pluripotent stem cells have been shown, by a variety of approaches, to have an open chromatin state with reduced levels of heterochromatin, both in vitro and in vivo. This open chromatin state is thought to be important for the maintenance of pluripotency.
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Open chromatin may be regulated by several chromatin regulators that are abundant in embryonic stem cells. These factors seem to actively prevent heterochromatin from expanding in the undifferentiated state.
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In the context of a globally open chromatin, other chromatin regulators contribute locally to the silencing of lineage-specific genes until differentiation is triggered, keeping pluripotent stem cells in a poised undifferentiated state.
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Reprogramming of somatic cells to pluripotent stem cells requires re-opening of chromatin in a process that probably involves some of the same factors that maintain open chromatin. Chromatin re-opening during reprogramming may not always be complete and thus leaves an epigenetic memory of the original cell type.
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The overcoming of epigenetic barriers during somatic cell reprogramming to pluripotency appears to have molecular parallels with cellular transformation in cancer.
Abstract
Pluripotent stem cells can be derived from embryos or induced from adult cells by reprogramming. They are unique among stem cells in that they can give rise to all cell types of the body. Recent findings indicate that a particularly 'open' chromatin state contributes to maintenance of pluripotency. Two principles are emerging: specific factors maintain a globally open chromatin state that is accessible for transcriptional activation; and other chromatin regulators contribute locally to the silencing of lineage-specific genes until differentiation is triggered. These same principles may apply during reacquisition of an open chromatin state upon reprogramming to pluripotency, and during de-differentiation in cancer.
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Change history
23 March 2011
In the reference list for this article, reference 39 was incorrect. The reference should have been "Azuara V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532–538 (2006)". The authors apologize for this error.
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Acknowledgements
We thank E. Bernstein, F. M. Koh, M. Sachs and three anonymous reviewers for constructive comments. E.M. is a Joseph H. and Belle R. Braun senior lecturer in life sciences and is supported by the Israel Science Foundation (ISF 215/07 and 943/09), the Israel Cancer Research Foundation, the Israel Ministry of Health (6007), the European Union (IRG-206872 and 238176) and an Alon Fellowship. A.A. is a Safra fellow. Work in the M.R.-S. laboratory is supported by a US National Institutes of Health Director's New Innovator Award, the California Institute for Regenerative Medicine and the Helmsley Trust.
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Glossary
- Endoderm
-
The innermost of the three germ layers that are formed during embryonic development. Prominent examples of endodermal tissues include the epithelia of the gastrointestinal and respiratory tracts, thyroid, liver and pancreas, as well as of the auditory and urinary systems.
- Mesoderm
-
The middle of the three germ layers that are formed during embryonic development. Prominent examples of mesodermal tissues include bone, cartilage, blood, muscle, heart, connective tissue and kidney.
- Ectoderm
-
The outermost of the three germ layers that are formed during embryonic development. Prominent examples of ectodermal tissues include the nervous system, hair, skin, nails and eyes, as well as the various derivatives of the neural crest, including bones of the head and peripheral nerves.
- Heterochromatin
-
Highly compacted chromatin that is transcriptionally inactive. Includes structural regions of the chromosome, such as centromeres, that lack genes ('constitutive' heterochromatin) and regions in which genes are silenced in a given cell type ('facultative' heterochromatin).
- Euchromatin
-
A form of chromatin that is relatively decondensed and often transcriptionally active during interphase.
- Electron spectroscopic imaging
-
(ESI). Energy-filtered transmission electron microscopy, in which the image is formed only by electrons transmitted within a certain energy window. It allows direct quantitative imaging of elements within the specimen.
- Embryoid body
-
(EB). A cellular aggregate that is produced when ES cells are induced to differentiate in non-adherent conditions that mimic the early stages of embryogenesis.
- ChIP–chip
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Chromatin immunoprecipitation (ChIP) followed by microarray. ChIP is a method that allows isolation of DNA sequences that are bound to a protein of interest using specific antibodies. DNA isolated by ChIP is denatured and hybridized to a tiling array, which typically includes probes covering the entire genome. Paired probes indicate that the protein of interest was bound to that particular region of DNA.
- ChIP–seq
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Chromatin immunoprecipitation (ChIP) followed by sequencing. Refers to high-throughput sequencing of ChIP-isolated DNA, and provides genome-wide information of the DNA binding sites of the protein of interest.
- Heterochromatin protein 1
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(HP1). A heterochromatin-binding protein that recognizes and binds to histone H3 tri-methylated on Lys9. It includes three isoforms (α, β and γ), which are encoded by three different genes (CBX5, CBX1 and CBX3, respectively).
- Proteasome
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A large multisubunit protein complex that degrades proteins. Undesired proteins are labelled for degradation by the addition of a chain of the small protein ubiquitin; a process that is mediated by a family of enzymes called ubiquitin ligases.
- CpG island
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A genomic region which contains a high content of cytosine (C) and guanine (G) dinucleotides (the 'p' refers to the phosphodiester bond linking the two bases). CpG islands are found in many mammalian promoters, and unlike scattered CpGs throughout the genome, which are usually hypermethylated, promoter CpG islands are normally hypomethylated.
- Helicase
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A protein that can unwind DNA or RNA.
- Teratoma
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A confined tumour, originating from pluripotent cells, that includes tissues of the three germ layers, endoderm, mesoderm and ectoderm.
- Telomeric region
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A region of repetitive DNA at the ends of chromosomes that protects the chromosomes from premature deterioration, rearrangements and chromosome fusion.
- Histone hyperacetylation
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A state in which many Lys residues are acetylated on many of the histones present in a given region of chromatin.
- Genetic epistasis
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The relationship or order in which two genes act in a pathway (that is, upstream or downstream, synergistic or antagonistic), which can be studied by analysing single and double mutants.
- DamID
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A method that is used to analyse binding of proteins to DNA. Genetically modified Drosophila melanogaster culture cell lines express a protein of interest fused with a bacterial DNA adenine methyltransferase. Local DNA methyltransferase activity indicates protein binding.
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Gaspar-Maia, A., Alajem, A., Meshorer, E. et al. Open chromatin in pluripotency and reprogramming. Nat Rev Mol Cell Biol 12, 36–47 (2011). https://doi.org/10.1038/nrm3036
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DOI: https://doi.org/10.1038/nrm3036
