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Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control

Key Points

  • X-chromosome inactivation (XCI), a process that was discovered by Mary Lyon 50 years ago, has become a model system for the cell biological mechanisms that regulate non-coding RNAs and chromatin during gene expression.

  • XCI occurs as a continual biological cycle that begins during both oogenesis and spermiogenesis, allowing 'imprinted' XCI upon zygote formation, and must then be re-established in a 'random' manner at the epiblast stage of development.

  • The mechanisms that drive XCI revolve around the nucleation of an inactive state at the X-inactivation centre (Xic), and require regulatory networks of non-coding sense and antisense RNAs that drive expression of the X-inactivation specific transcript (Xist) transcript on the future inactive X chromosome through RNA–RNA and RNA–protein interactions. Less is known about how Xist RNA spreads from the 'nucleation centre' to induce heterochromatin elsewhere on the inactive X chromosome.

  • XCI has also provided key insights into nuclear structure and function, in terms both of how chromosome territory organization controls gene expression and of the means by which certain genes on the X chromosome escape from inactivation. The transient X–X pairing that occurs before XCI also provides an unusual example of somatic chromosome pairing in mammals, and this may be important for generating epigenetic asymmetry between the two X chromosomes.

  • The characterization of long non-coding RNAs (lncRNAs) that reside at the Xic has provided a model for the unique properties of lncRNAs, which enable locus-specific control during gene expression. The regulatory principles that have emerged here are likely to be relevant for lncRNA functions throughout the genome.


The discovery of X-chromosome inactivation (XCI) celebrated its golden anniversary this year. Originally offered as an explanation for the establishment of genetic equality between males and females, 50 years on, XCI presents more than a curious gender-based phenomenon that causes silencing of sex chromosomes. How have the mysteries of XCI unfolded? And what general lessons can be extracted? Several of the cell biological mechanisms that are used to establish the inactive X chromosome, including regulatory networks of non-coding RNAs and unusual nuclear dynamics, are now suspected to hold true for processes occurring on a genome-wide scale.

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Figure 1: The XCI cycle.
Figure 2: Non-coding genes of the Xic.
Figure 3: Molecular events at the initiation of XCI.
Figure 4: Transient X–X pairing enables a break in symmetry to initiate XCI.
Figure 5: RNAs are ideally suited to cis-regulation and locus-specific control.


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I am greatly indebted to members of the laboratory, past and present, for their valuable intellectual and experimental contributions. I also thank A. Riggs, B. Payer and Y. Jeon for critical reading of the manuscript, and the Howard Hughes Medical Institute for providing ongoing support.

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Dosage compensation

A process by which the expression of sex-linked genes is equalized in species in which males and females differ in the number of sex chromosomes.

One gene–one enzyme hypothesis

The view that an enzyme or protein is encoded by information in a single corresponding gene.


Of the nucleolus, which is a conserved organelle that assembles around ribosomal DNA genes and is the site of ribosomal RNA transcription and the assembly of ribosome subunits (the translation machinery).


Instances in which an abnormal number of chromosomes are generated during cell division because the chromosomes do not separate properly between the two daughter cells. This is a characteristic of cancer cells.


The inner layer of the developing vertebrate embryo that gives rise to the fetus.


A genetic mechanism by which genes are selectively expressed from the maternal or paternal chromosomes.


The embryo form before implantation that contains at least two distinct cell types: the trophectoderm and the inner cell mass.


The innermost germ layer of the developing embryo. 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.


(TE). An extra-embryonic lineage that is derived from the outer layer of cells within the blastocyst.

Embryonic stem cells

(ES cells). Pluripotent cells that can be derived from the inner cell mass of the blastocyst-stage embryo.

Primordial germ cells

(PGCs). Cells that have the ability to self-renew and to generate differentiated cells that are restricted to the germ cell lineage.

Genital ridges

Mesodermal precursors to the somatic gonads in vertebrate embryos (also known as gonadal ridges).

Facultative heterochromatin

A dynamic subtype of heterochromatin that is inducible and is formed from a euchromatic environment, where heterochromatin proteins are used to stably repress the activity of certain target genes.


(Long interspersed nuclear elements). Long interspersed sequences that contain a promoter region, an untranslated region and one or more open reading frames and are generated by retrotransposition.


(Short interspersed nuclear elements). Short interspersed sequences that are generated by RNA polymerase III transcripts.

Chromosome territory

A domain of the nucleus that is occupied by a pair of homologous chromosomes.

Chromatin insulators

Complexes, formed from chromatin elements and their associated proteins, that act as barriers against the influence of positive (enhancers) or negative (silencers) signals.


A technique in which transcripts are immunoprecipitated through their association with a chromatin modifier or other protein, reverse transcribed and then identified by high-throughput sequencing.

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Lee, J. Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat Rev Mol Cell Biol 12, 815–826 (2011).

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