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X-chromosome inactivation: counting, choice and initiation

Abstract

In many sexually dimorphic species, a mechanism is required to ensure equivalent levels of gene expression from the sex chromosomes. In mammals, such dosage compensation is achieved by X-chromosome inactivation, a process that presents a unique medley of biological puzzles: how to silence one but not the other X chromosome in the same nucleus; how to count the number of X's and keep only one active; how to choose which X chromosome is inactivated; and how to establish this silent state rapidly and efficiently during early development. The key to most of these puzzles lies in a unique locus, the X-inactivation centre and a remarkable RNA — Xist — that it encodes.

Key Points

  • In mammals, dosage compensation involves silencing one of the two X chromosomes early during female development — a process known as X inactivation.

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

  • A key gene within Xic is Xist, which encodes a non-coding nuclear RNA. Xist RNA is essential for X inactivation and coats the X early during the inactivation process

  • Antisense transcription across Xist (leading to production of the Tsix transcript) is thought to be important in the regulation of Xist expression and in mechanisms of choice in X inactivation.

  • Several events occur after Xist expression and are thought to stabilize the inactivity of the chromosome. Comparisons with Drosophila indicate that Xist might help to recruit protein complexes to the inactiving chromosome.

  • Further (and later) features of the inactive X include hypermethylation of DNA, histone deacetylation, chromatin condensation, late replication and association with the variant histone macroH2A.

  • X inactivation is imprinted in extra-embryonic tissues of eutherian mammals. The paternal chromosome is preferentially inactivated and this might reflect the special state of the genome after passage through the paternal genome. Maternal imprinting of the X chromosome also contributes to preferential inactivation.

  • There is some evidence that repeats such as LINE-1 elements might influence the spreading of inactivity from the Xic.

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Figure 1: The X-inactivation centre.
Figure 2: Xist transcription in embryonic stem cells.
Figure 3: Potential roles for Xist antisense transcription.
Figure 4: Imprinted versus random X inactivation.
Figure 5: A model for X inactivation.

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DATABASE LINKS

Xce

Xist

Tsix

roX1

roX2

MLE

MSL-1

MSL-2

MSL-3

MOF

DNMT3B

ICF syndrome

MECP2

Rett syndrome

ENCYCLOPEDIA OF LIFE SCIENCES

X-chromosome inactivation

X-inactivation mechanisms

Glossary

CHROMODOMAIN

A highly conserved sequence motif that has been identified in various animal and plant species. Chromodomain proteins seem to be either structural components of large macromolecular chromatin complexes or involved in remodelling chromatin structure.

MACROCHROMATIN BODY

(MCB). Discrete accumulation of the histone variant, macroH2A, on the inactive X chromosome.

CENTROSOME

The microtubule organizing centre that divides to organize the two poles of the mitotic spindle and directs assembly of the cytoskeleton, thus controlling cell division, motility and shape.

EUTHERIANS

Mammals that give birth to live offspring (viviparous) and possess an allantoic placenta.

TROPHECTODERM

The precursor to the bulk of the embryonic part of the placenta.

SEX VESICLE OR XY BODY

Pairing of sex chromosomes during meiosis in male mammals is associated with heterochromatinization and occurs in the sex vesicle or XY-body, a specific nuclear structure that can be discerned morphologically.

ANDROGENONE

Embryo with two paternal sets of chromosomes.

UNIPARENTAL DISOMIC

An individual or embryo carrying two chromosomes inherited from the same parent

LINES

Long interspersed nuclear elements (such as L1 repeats) are retroelements present in over 100,000 copies in the mammalian genome.

REPEAT-INDUCED GENE SILENCING

(RIGS). Transgene expression in several organisms may be silenced epigenetically when repeated sequences are present. It has been proposed that interactions between homologous sequences (repeats) might lead to the formation of folded chromatin structures that attract heterochromatin-specific macromolecules

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Avner, P., Heard, E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2, 59–67 (2001). https://doi.org/10.1038/35047580

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