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Regulation of X-chromosome inactivation by the X-inactivation centre

Nature Reviews Genetics volume 12, pages 429–442 (2011)Cite this article

Subjects

Key Points

  • X-chromosome inactivation (XCI) is controlled by a complex locus termed the X-inactivation centre (Xic).

  • Chromosome-wide silencing is triggered through expression of Xist, a long non-coding RNA (ncRNA) that is upregulated on one of the two X chromosomes in differentiating XX cells.

  • XCI can be imprinted or random, and both forms require Xist but have different Xic requirements.

  • During random XCI, the Xist promoter is repressed, directly or indirectly, by a combination of factors including pluripotency factors, which ensure that Xist is only expressed in differentiated cells.

  • Several X-linked elements/factors ensure that Xist is upregulated only in cells with more than one X chromosome.

  • Monoallelic Xist expression may be regulated by several mechanisms, including: imprinting (maternal repression); low probability of Xist activation followed by an Xist-mediated negative feedback loop; secondary selection against aberrant XCI patterns; asymmetry introduced when physical interactions between the Tsix alleles occur; and the existence of posed asymmetric and switchable fates between the two X chromosomes before XCI.

  • The X/autosome (X/A) ratio influences the number of X chromosomes that will remain active during random XCI, so that diploid cells only keep one active X chromosome and tetraploid cells tend to keep two active X chromosomes, irrespective to their total X chromosome number.

  • The inactive state of the X chromosome can be reversed in specific tissues and at specific stages of development, as well as during cloning or induced pluripotency experiments in mice.

  • Different mammals may exploit different mechanisms of Xist regulation during early embryogenesis.

Abstract

X-chromosome inactivation (XCI) ensures dosage compensation in mammals and is a paradigm for allele-specific gene expression on a chromosome-wide scale. Important insights have been made into the developmental dynamics of this process. Recent studies have identified several cis- and trans-acting factors that regulate the initiation of XCI via the X-inactivation centre. Such studies have shed light on the relationship between XCI and pluripotency. They have also revealed the existence of dosage-dependent activators that trigger XCI when more than one X chromosome is present, as well as possible mechanisms underlying the monoallelic regulation of this process. The recent discovery of the plasticity of the inactive state during early development, or during cloning, and induced pluripotency have also contributed to the X chromosome becoming a gold standard in reprogramming studies.

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Figure 1: The X-inactivation centre.
Figure 2: The cycle of XCI in female mouse embryos and ESCs.
Figure 3: Summary of Xist regulation at the onset of XCI.
Figure 4: Models for monoallelic regulation of Xist.

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Acknowledgements

We would like to thank all of our colleagues in the Mammalian Developmental Epigenetics team for their discussions and input and extend our apologies to any authors whose work could not be discussed owing to space constraints. Our work is supported by the FRM, ANR, ARC, the EU Integrated projects HEROIC and SYBOSS, EU Networks of excellence Epigenome and Epigenesys, as well as an ERC Advanced Investigator award.

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  1. Sandrine Augui and Elphège P. Nora: These authors contributed equally to this work.

Authors and Affiliations

  1. Mammalian Developmental Epigenetics Group, Unit of Genetics and Developmental Biology, Institut Curie, CNRS UMR3215, INSERM U934, Paris, F-75248, France

    Sandrine Augui, Elphège P. Nora & Edith Heard

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Glossary

Homogametic and heterogametic sexes

In species with sexual dimorphism, the sex that can produce two different types of gametes (X and Y or Z and W) is called heterogametic, whereas the sex that can produce only one type of gamete (X or Z) is called homogametic.

Imprinted

Epigenetic marking of a locus on the basis of its parental origin, which can result in differential expression of the paternal and maternal alleles in specific tissues or developmental stages.

Polycomb group proteins

(PcG proteins). A class of proteins — originally described in Drosophila melanogaster — that form large complexes and maintain the stable and heritable repression of several genes throughout development.

Trithorax group proteins

(TrxG proteins). A class of proteins — originally described in Drosophila melanogaster — that form large complexes and maintain the stable and heritable expression of several genes throughout development.

Pluripotency factors

A class of proteins that — maintain pluripotency the capacity to give rise to a wide range of, but not all, cell lineages — of stem cells.

Dicer

An RNase III family endonuclease that processes dsRNA and precursor microRNAs into small interfering RNAs and microRNAs, respectively.

CCCTC-binding factor

(CTCF). A highly conserved DNA-binding protein with 11 zinc fingers that, in mammalian genomes, binds to regulatory elements such as insulators.

Eutherians

Mammals in which the development of progeny takes place in the mother's body thanks to the placenta, a fetal membrane that facilitates nutrient and waste exchange between the fetus and the mother.

Meiotic sex chromosome inactivation

(MSCI). Silencing and hetero-chromatinization of sex chromosomes in the male germ line during meiosis.

Androgenetic

Androgenetic embryos are produced by the fusion of two haploid paternal genomes.

Parthenogenote

A uniparental embryo produced by the development of an unfertilized egg.

Gynogenote

An embryo produced by the fusion of two haploid maternal genomes.

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Augui, S., Nora, E. & Heard, E. Regulation of X-chromosome inactivation by the X-inactivation centre. Nat Rev Genet 12, 429–442 (2011). https://doi.org/10.1038/nrg2987

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