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Gene regulation in time and space during X-chromosome inactivation

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From Nature Reviews Molecular Cell Biology

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Abstract

X-chromosome inactivation (XCI) is the epigenetic mechanism that ensures X-linked dosage compensation between cells of females (XX karyotype) and males (XY). XCI is essential for female embryos to survive through development and requires the accurate spatiotemporal regulation of many different factors to achieve remarkable chromosome-wide gene silencing. As a result of XCI, the active and inactive X chromosomes are functionally and structurally different, with the inactive X chromosome undergoing a major conformational reorganization within the nucleus. In this Review, we discuss the multiple layers of genetic and epigenetic regulation that underlie initiation of XCI during development and then maintain it throughout life, in light of the most recent findings in this rapidly advancing field. We discuss exciting new insights into the regulation of X inactive-specific transcript (XIST), the trigger and master regulator of XCI, and into the mechanisms and dynamics that underlie the silencing of nearly all X-linked genes. Finally, given the increasing interest in understanding the impact of chromosome organization on gene regulation, we provide an overview of the factors that are thought to reshape the 3D structure of the inactive X chromosome and of the relevance of such structural changes for XCI establishment and maintenance.

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Fig. 1: The X-inactivation centre and the initiation of X-chromosome inactivation.
Fig. 2: Epigenetic dynamics during X-chromosome inactivation.
Fig. 3: Molecular mechanisms of X-chromosome inactivation.
Fig. 4: Structural and functional differences between the active and inactive X chromosomes.

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Acknowledgements

The authors thank T. Pollex for critical reading of the manuscript. They apologize to all the authors whose original work they could not cite here owing to space constraints. Work in the Heard laboratory is supported by a European Research Council Advanced Investigator award (XPRESS — AdG671027). A.L. is supported by a European Union Marie Skłodowska-Curie Actions Individual Fellowship (IF-838408).

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    Agnese Loda, Samuel Collombet & Edith Heard

  2. Collège de France, Paris, France

    Edith Heard

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Glossary

Topologically associating domains

(TADs). Submegabase chromosomal domains in which genomic elements interact preferentially with each other.

Hi-C

A chromosome conformation capture-based method to characterize the 3D organization of the whole genome.

Facultative heterochromatin

Developmentally regulated stable silencing of parts of the genome, in the case of X-chromosome inactivation, across one of two homologous X chromosomes.

4C

A chromosome conformation capture-based method to characterize the interactions between one genomic locus of interest and the rest of the genome.

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Loda, A., Collombet, S. & Heard, E. Gene regulation in time and space during X-chromosome inactivation. Nat Rev Mol Cell Biol 23, 231–249 (2022). https://doi.org/10.1038/s41580-021-00438-7

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