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Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation

Key Points

  • X-chromosome inactivation (XCI) silences one of the two X chromosomes in female mammals to achieve dosage compensation between the sexes.

  • Chromosome-wide silencing is initiated by the long non-coding X-inactivation specific transcript (Xist) RNA, which associates with the inactive X chromosome (Xi) and triggers chromatin modifications and gene silencing.

  • Association of Xist with the Xi leads to the formation of a repressive compartment over genomic repeat sequences within the centre of the Xi territory.

  • Gene silencing requires the repeat A sequence, which is located at the 5′ end of Xist, and silencing factors such as special AT-rich sequence binding protein 1 (SATB1).

  • In development, silencing on the Xi becomes stabilized and does not require continuous Xist expression in somatic cells.

  • DNA methylation and structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1) are required for the maintenance of gene repression in somatic cells.

  • The facultative heterochromatin of the Xi is characterized by several chromatin components — including Polycomb group complexes — that make it distinct from other heterochromatin in the cell nucleus.

  • Reactivation of the Xi is observed at certain stages of development, such as in the formation of the female germ cells. It also occurs during experimentally induced reprogramming of induced pluripotent stem cells.

Abstract

In female mammals, one of the two X chromosomes is silenced for dosage compensation between the sexes. X-chromosome inactivation is initiated in early embryogenesis by the Xist RNA that localizes to the inactive X chromosome. During development, the inactive X chromosome is further modified, a specialized form of facultative heterochromatin is formed and gene repression becomes stable and independent of Xist in somatic cells. The recent identification of several factors involved in this process has provided insights into the mechanism of Xist localization and gene silencing. The emerging picture is complex and suggests that chromosome-wide silencing can be partitioned into several steps, the molecular components of which are starting to be defined.

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Figure 1: X-chromosome inactivation and reactivation during mouse development.
Figure 2: Xist localization to the X chromosomes.
Figure 3: Initiation of chromosome-wide silencing on the inactive X chromosome.
Figure 4: Transition to maintenance of X-chromosome inactivation.

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Acknowledgements

The author is the recipient of a Wellcome Trust Senior Research Fellowship (grant reference 087530/Z/08/A).

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Glossary

Dosage compensation

In mammals, the difference in chromosome complement between XY males and XX females is compensated by transcriptional silencing of genes on one of the two X chromosomes in female cells. Therefore, in both male and female cells, a single copy of each of the X-linked genes is active; this is in contrast to autosomal genes, which are expressed from two homologous chromosomes.

Facultative heterochromatin

A subtype of heterochromatin that is formed in the euchromatic environment, in which heterochromatin proteins are used to stably repress the activity of certain target genes.

Chromosome territory

The volume occupied by the DNA of a single chromosome in the interphase cell nucleus.

Polycomb group complex

(PcG complex). A chromatin-modifying complex that contains proteins that were originally indentified as being required for maintenance of homeotic gene silencing in Drosophila melanogaster.

Nuclear scaffold

A network within the nucleus consisting of RNA and protein that is believed to organize chromatin.

Long interspersed elements

(LINEs). Types of repetitive DNA in animal genomes that are derived from transposons.

Blastocysts

Pre-implantation embryonic stages that are characterized by the first definitive lineages. They consist of a fluid-filled cavity (blastocoel), a focal cluster of cells from which the embryo will develop (inner cell mass) and peripheral trophoblast cells, which form the placenta.

Pericentric heterochromatin

A block of heterochromatin-containing silent repeats surrounding the centromeres of the chromosomes.

Thymocytes

A subset of white blood cells (T cells) that reside in the thymus. Thymocytes perform functions in the immune response.

Imprinted XCI

(Imprinted X-chromosome inactivation). Inactivation of the paternally inherited X chromosome, whereby inactivation is determined by the parental origin of the chromosome.

Trophoblast

An extra-embryonic lineage that is derived from the trophectoderm of the blastocyst, which gives rise to a cell layer of the placenta.

Histone variant

A protein that contains a histone domain and, in addition, another unrelated protein domain.

Trithorax protein

A protein that maintains the stable and heritable active state of several genes, including the homeotic genes. Trithorax group proteins were discovered in genetic screens in Drosophila melanogaster, in which they were found to oppose the silencing mediated by Polycomb group complexes.

Primordial germ cells

Embryonic cells that give rise to germ cells from which the haploid gametes (oocytes in females and sperm in males) differentiate.

Inner cell mass

A small clump of cells in the blastocyst, which gives rise to the entire fetus plus some of its extra-embryonic membranes.

Pluripotent

A term used to describe a cell that has the developmental potential to differentiate into all lineages of the embryo, including the germ cells.

Epiblast

A term for the group of embryonic cells from which the embryo is structured during gastrulation. It is derived from the inner cell mass of the blastocyst.

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Wutz, A. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet 12, 542–553 (2011). https://doi.org/10.1038/nrg3035

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