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The X chromosome in space

Key Points

  • Spatial interactions between RNA, architectural factors and chromatin have essential roles during X-chromosome inactivation.

  • CTCF is a versatile factor that regulates chromosome counting, allelic pairing, allelic choice and X-chromosome architecture.

  • Xist RNA determines the 3D structure of the inactive X chromosome by evicting architectural proteins.

  • The active X chromosome is organized into more than 100 topologically associated domains (TADs), whereas the inactive X chromosome is partitioned into two megadomains.

  • Spatial partitioning of the X-inactivation centre into two TADs allows proper Xist and Tsix expression during X-chromosome inactivation.

  • Perinucleolar localization of the inactive X chromosome helps to maintain its epigenetic state.


Extensive 3D folding is required to package a genome into the tiny nuclear space, and this packaging must be compatible with proper gene expression. Thus, in the well-hierarchized nucleus, chromosomes occupy discrete territories and adopt specific 3D organizational structures that facilitate interactions between regulatory elements for gene expression. The mammalian X chromosome exemplifies this structure–function relationship. Recent studies have shown that, upon X-chromosome inactivation, active and inactive X chromosomes localize to different subnuclear positions and adopt distinct chromosomal architectures that reflect their activity states. Here, we review the roles of long non-coding RNAs, chromosomal organizational structures and the subnuclear localization of chromosomes as they relate to X-linked gene expression.

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Figure 1: The potential roles of long non-coding RNAs in the initiation of X-chromosome inactivation.
Figure 2: The 3D organization of X chromosomes.
Figure 3: Models for the position of silent and escapee genes on the Xi.
Figure 4: Organization of the DXZ4 and Dxz4 loci in human and mouse models, respectively.
Figure 5: The X-inactivation centre is partitioned into two topologically associated domains.
Figure 6: The X chromosome in space.


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The authors thank M.-E. Gilles, Y. Jeon and F. Ariel for many inspirational discussions. T.J. is a European Molecular Biology Organization (EMBO) postdoctoral fellow (EMBO ALTF 1313–2015); E.A. is funded by the Swiss National Science Foundation. J.T.L. is funded by the US National Institutes of Health (R37-GM58839) and is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Jeannie T. Lee.

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PowerPoint slides


X-chromosome inactivation

(XCI). A process to epigenetically silence one X chromosome in the somatic cells of female mammals to achieve similar expression levels between the sexes.

Long non-coding RNAs

(lncRNAs). Transcripts of more than 200 nucleotides that do not encode proteins.


(X-inactive specific transcript). A long non-coding RNA that is transcribed from the X-inactivation centre and is the key regulator of mouse X-chromosome inactivation.


(CCCTC-binding factor). A highly conserved DNA-binding protein that regulates chromatin organization and is involved in transcriptional regulation and insulation.


A DNA sequence element that blocks heterochromatin spreading and interaction between enhancers and promoters.

Chromosome territories

The domains occupied by chromosomes in the interphase cell nucleus.


Cells containing genetically different nuclei.

Sponge-like structure

(Also called a porous structure). A model of chromosome territory structure in which chromolome territories are composed of interconnected chromatin domains permeated by an interchromatin channel.

Interchromatin channels

Channels that pervade chromatin domain clusters both between and within chromosome territories. The channels are a chromatin-free compartment containing RNA polymerase II, transcription factories, splicing speckles and architectural proteins.

Chromatin domain clusters

(CDCs). Groups of chromatin domains that comprise the inactive nuclear compartment.

Perichromatin region

The decondensed and transcriptionally competent chromatin region residing at the periphery of chromatin domain clusters.

Chromosome conformation capture

A technique to detect physical interactions between distant DNA sequences.

Topologically associated domains

(TADs). Units of chromatin that display a high frequency of DNA long-range interactions between loci located in the same unit and a low frequency of association between loci located in adjacent units.


A specific class of large tandem repeat DNA that is characterized by the large size of individual repeats, which can each be several kilobases long. Macrosatellites can span hundreds of kilobases of DNA.


Extremely long-range intrachromosomal contacts between two loci, up to 80 Mb long.


Protein complexes composed of the core subunits SMC3, SMC1, RAD21 and STAG1 (also known as SA1) or STAG2 (also known as SA2). Cohesin participates with CTCF to mediate long-range chromatin interactions.

Xist A-repeat region

A domain of Xist RNA that has been identified as necessary for Xist-mediated silencing but not for localization of Xist to the X chromosome.

Escapee genes

X-Linked genes that are biallelically expressed in female somatic cells.

Long interspersed nuclear elements

(LINEs). A type of repetitive DNA in the mammalian genome that is derived from transposons.

Nuclear periphery

A subcompartment of the nucleus that is composed of the nuclear-membrane bilayer, its associated proteins and the nuclear-pore complexes.

Lamina-associated domains

Genomic regions that interact with the nuclear lamina.

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Jégu, T., Aeby, E. & Lee, J. The X chromosome in space. Nat Rev Genet 18, 377–389 (2017).

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