Sex Chromosome Dosage Compensation

Abstract

Organisms that use a chromosome‐based mechanism for sex determination must contend with the resulting sex‐linked gene dosage imbalance between males and females. While some organisms appear to tolerate gene‐dosage differences, others have evolved compensatory processes. The molecular mechanisms behind dosage compensation are only understood in a few organisms. In the fruit fly Drosophila melanogaster, XY males upregulate X‐linked gene expression two‐fold by a process that involves histone acetylation. Whether other lineages upregulate the male X is currently highly debated. Then in mammals, XX females inactivate one of their two X chromosomes using the long noncoding RNA Xist and repressive chromatin modifications. In the nematode Caenorhabditis elegans, XX hermaphrodites downregulate gene expression from both X chromosomes two‐fold by the action of a protein complex resembling the mitotic chromosome compaction machinery. Detailed studies of these mechanisms provided insights into not just dosage compensation, but the broader field of gene regulation in general.

Key Concepts

  • Differences in sex chromosome dose create a gene expression imbalance.
  • Some lineages tolerate sex‐chromosome‐linked imbalances, other lineages evolved mechanisms to compensate for the differences in gene dosage.
  • Complete balance includes balancing the single male X to autosomes and equalising sex‐linked gene dosage between the sexes.
  • The MSL complex binds to the X chromosome in male Drosophila to upregulate gene expression two‐fold.
  • The MSL subunit MOF acetylates lysine 16 on histone H4 in gene bodies, leading to enhancement of transcription elongation.
  • The noncoding RNA Xist is expressed from the inactive X chromosome of female mammals.
  • Xist RNA recruits chromatin‐modifying activities to transcriptionally silence the chromosome.
  • The condensin‐like DCC binds both X chromosomes of hermaphroditic nematodes to dampen gene expression two‐fold.
  • The DCC remodels and compacts the chromosome and recruits histone‐modifying enzymes to limit RNA Polymerase II loading onto the chromosomes.

Keywords: dosage compensation; chromatin; epigenetics; noncoding RNA; histones; histone acetylation; histone methylation; condensin

Figure 1. Gene dosage imbalance. If the subunits of a protein complex are encoded on different chromosomes, chromosome copy number differences may result in protein imbalance between subunits and disrupt assembly of functional complexes. Subunits not incorporated into the complex (marked ‘?’) may have deleterious effects.
Figure 2. Summary of X:A (X chromosome to autosome) expression ratios. In the absence of dosage compensation, males will have reduced expression from the X compared to females. Male‐specific X upregulation balances the X to autosomes and equalizes X‐linked gene expression between the sexes. Nonsex‐specific X upregulation combined with a compensatory mechanism in XX animals (X‐inactivation or downregulation), also results in X:A balance and equal expression in both sexes. If upregulation is incomplete, but XX animals have compensatory processes, both sexes end up with underexpression of the X compared to autosomes. Green shading indicates X:A balance.
Figure 3. Male‐specific X upregulation in Drosophila melanogaster. (a) The MSL complex is first targeted to PionX sites on the male X (dark blue), then it spreads to other high‐affinity sites by exploiting the 3D‐conformation of the X chromosome, and finally, it spreads onto most actively transcribed genes (light blue). (b) Subunit composition and activity of the MSL complex and additional proteins contributing to X upregulation.
Figure 4. X chromosome inactivation in female mammals. (a) Xist RNA (red) is transcribed from the inactive X, and it spreads from the site of its transcription by taking advantage of the 3D‐folding of the chromosome. (b) Xist RNA recruits various chromatin‐modifying complexes to transcriptionally silence the chromosome.
Figure 5. X chromosome downregulation in C. elegans hermaphrodites. (a) The DCC initially binds to recruitment sites on the X chromosomes (dark blue) and brings these binding sites to close spatial proximity. From these recruitment sites, the DCC spreads to most genes on the chromosome (light blue). (b) Subunit composition and activities of the DCC and additional proteins contributing to two‐fold downregulation of transcription.
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Further Reading

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Csankovszki, Gyorgyi(Jul 2019) Sex Chromosome Dosage Compensation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005974]