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Chromatin modifiers and remodellers: regulators of cellular differentiation

Key Points

  • Embryonic stem (ES) cells have a globally 'open' and dynamic chromatin state.

  • Histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 'bivalency' is observed in ES cells that are cultured in the presence of serum, which could reflect cellular heterogeneity to a great extent. Bivalency is not a universal or unique feature of pluripotent and multipotent cells.

  • ES cell differentiation is accompanied by global chromatin remodelling, which results in a progressive transition from a fairly open chromatin configuration to a more compact and repressive state.

  • Dynamic changes in histone modifications also occur during adult stem cell differentiation.

  • Genetic studies in knockout mice suggest major roles for various chromatin modifiers and remodellers in key developmental transitions, such as the segregation of embryonic (that is, the inner cell mass) and extra-embryonic (that is, the trophoblast) lineages at the blastocyst stage, and the formation of the three germ layers (that is, the ectoderm, mesoderm and endoderm) during gastrulation.

  • Epigenetic 'pre-patterning' in pluripotent and multipotent cells may be important in lineage specification.

  • Chromatin modifiers often exist in multisubunit co-regulator complexes. The heterogeneous compositions of these complexes contribute to target selectivity and to functional specificity.

  • Some classic 'co-repressors' are associated with actively transcribed loci, which may prevent cryptic initiation of transcription and may 'fine-tune' transcription.

  • Recent evidence suggests that, at least in some cases, histone methylation enzymes, rather than histone methylation marks, persist through DNA replication, which provides a possible mechanism for the inheritance of histone modifications.

Abstract

Cellular differentiation is, by definition, epigenetic. Genome-wide profiling of pluripotent cells and differentiated cells suggests global chromatin remodelling during differentiation, which results in a progressive transition from a fairly open chromatin configuration to a more compact state. Genetic studies in mouse models show major roles for a variety of histone modifiers and chromatin remodellers in key developmental transitions, such as the segregation of embryonic and extra-embryonic lineages in blastocyst stage embryos, the formation of the three germ layers during gastrulation and the differentiation of adult stem cells. Furthermore, rather than merely stabilizing the gene expression changes that are driven by developmental transcription factors, there is emerging evidence that chromatin regulators have multifaceted roles in cell fate decisions.

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Figure 1: Chromatin states in pluripotent and differentiated cells.
Figure 2: Chromatin regulators that are involved in the segregation of embryonic and extra-embryonic lineages during pre-implantation development.
Figure 3: Chromatin regulators that are involved in gene regulation during post-implantation development and cellular differentiation.
Figure 4: Epigenetic 'pre-patterning' for lineage specification.
Figure 5: Inheritance of DNA methylation and histone methylation marks through DNA replication.

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Acknowledgements

Work in T.C.'s laboratory is supported by the Cancer Prevention and Research Institute of Texas (CPRIT). T.C. is a CPRIT Scholar in Cancer Research; S.Y.R.D.'s support includes two grants from the US National Institutes of Health, GM067718 and GM096472.

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Correspondence to Taiping Chen or Sharon Y. R. Dent.

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Glossary

Cytosine methylation

The addition of a methyl group to the fifth carbon in cytosine, which predominantly occurs in the context of CpG dinucleotides ('p' refers to the phosphodiester bond that links a cytosine and a guanine). It is often referred to as DNA methylation and is a major form of DNA modification. Promoter methylation correlates with gene silencing.

Cytosine hydroxymethylation

A form of DNA modification that is generated by the oxidation of 5-methylcytosine, which is mediated by the TET family of hydroxylases. 5-hydroxymethylcytosine is an intermediate in DNA demethylation and may also be a stable epigenetic mark.

Non-coding RNA

(ncRNA). A functional RNA molecule that is not translated into proteins and that can regulate gene expression at various levels, such as transcription, splicing, mRNA stability and translation. ncRNAs include small ncRNAs (for example, microRNAs and siRNAs) and long ncRNAs (for example, X inactive specific transcript (XIST) and HOXA transcript antisense RNA (HOTAIR)).

Pluripotency

The ability of a cell to differentiate into all three germ layers (that is, the endoderm, mesoderm and ectoderm) and to give rise to all fetal or adult cell types (for example, cells of the inner cell mass of blastocyst stage embryos are pluripotent).

Polycomb group

(PcG). A family of chromatin regulatory proteins that are typically involved in repressing gene expression, partly through the trimethylation of histone H3 lysine 27 and the monoubiquitylation of histone H2A lysine 119.

Trithorax group

A family of chromatin regulatory proteins that typically activate gene expression through the trimethylation of histone H3 lysine 4 and/or ATP-dependent chromatin remodelling.

Chromatin dynamics

Changes in chromatin structure, composition and positioning.

Inner cell mass

(ICM). A group of cells inside a mammalian blastocyst that gives rise to the embryo.

Blastocysts

Early stage embryos that have undergone the first cell lineage specification, which results in two primary cell types: cells of the inner cell mass and the trophoblasts.

Heterochromatin

Highly condensed chromatin that is transcriptionally inactive.

Major satellite DNA

Tandem repeating DNA sequences that are primarily present in the pericentromeric regions of the mouse genome.

Constitutive heterochromatin

Structural regions of chromosomes, such as the centromeres and the telomeres, that are devoid of genes.

Multipotent

Pertaining to the ability of a cell to differentiate into multiple but a limited range of cell types (for example, cells of the embryonic germ layers and adult stem cells are multipotent).

Facultative heterochromatin

Tightly packed chromatin regions in which genes are silenced in a given cell type.

Zygote

The fertilized egg before cleavage occurs; that is, the one-cell stage embryo.

Totipotent

Pertaining to the ability of a cell to give rise to differentiated cells of all tissues, including embryonic and extra-embryonic tissues, in an organism (for example, a zygote is totipotent).

Implantation

An early developmental stage at which the embryo adheres to the wall of the uterus.

Trophoblast

The outer layer of the mammalian blastocyst that eventually develops to form part of the placenta.

Ectoderm

The outermost layer of the three embryonic germ layers that gives rise to the epidermis (for example, the skin, hair and eyes) and the nervous system.

Mesoderm

The middle layer of the three embryonic germ layers that gives rise to the muscle, cartilage, bone, blood, connective tissue and so on.

Endoderm

The innermost layer of the three embryonic germ layers that gives rise to the epithelia of the digestive and respiratory systems, liver, pancreas and so on.

Gastrulation

A phase of early embryonic development during which the three germ layers are formed.

Nucleosome remodelling and deacetylation (NuRD) co-repressor complex

A multisubunit complex with both ATP-dependent chromatin remodelling and histone deacetylase activities. Its components include the chromodomain-helicase DNA-binding protein (CHD) family of ATPases Mi-2α/Mi-2β; histone deacetylase 1 (HDAC1) and HDAC2; metastasis-associated protein 1 (MTA1), MTA2 and MTA3; methyl CpG-binding protein 2 (MBD2) and MBD3; and histone-binding protein RBBP7 and RBBP4.

Leukaemia inhibitory factor

(LIF). An interleukin-6 class cytokine that is often added in mouse embryonic stem cell cultures to inhibit differentiation.

Trophoblast stem cell

A multipotent cell that can produce all trophoblast cell types in culture and in vivo.

Hatch

When a blastocyst bursts out of the protective zona pellucida.

Zona pellucida

A thick glycoprotein membrane that surrounds the plasma membrane of an oocyte.

Euchromatin

A form of chromatin that is fairly decondensed and is transcriptionally active.

SAGA complex

A multisubunit complex that is named after the yeast Spt-Ada-Gcn5 acetyltransferase complex and that is conserved in eukaryotic organisms. It has histone acetyltransferase activity that is mediated by the GCN5 subunit and histone deubiquitylase activity that is mediated by the ubiquitin carboxyl-terminal hydrolase 22 (USP22) subunit. It also contains subunits that are important for interactions with transcriptional activators and with the general transcription machinery; it functions as a co-activator.

Dedifferentiation

Conversion of a differentiated cell to a pluripotent or multipotent cell.

CpG islands

Genomic regions that contain a high content of CpG dinucleotides and that are found in many mammalian promoters.

Epiblast-derived stem cells

(EpiScs). Pluripotent stem cells that are derived from the late epiblast layer of post-implantation embryos.

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Chen, T., Dent, S. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet 15, 93–106 (2014). https://doi.org/10.1038/nrg3607

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