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Review
. 2015 Jan 1:3:1-19.
doi: 10.7150/jgen.10404. eCollection 2015.

Mechanisms of x chromosome dosage compensation

Sevinç Ercan  1
Affiliations
Review

Mechanisms of x chromosome dosage compensation

Sevinç Ercan. J Genomics. .

Abstract

In many animals, males have one X and females have two X chromosomes. The difference in X chromosome dosage between the two sexes is compensated by mechanisms that regulate X chromosome transcription. Recent advances in genomic techniques have provided new insights into the molecular mechanisms of X chromosome dosage compensation. In this review, I summarize our current understanding of dosage imbalance in general, and then review the molecular mechanisms of X chromosome dosage compensation with an emphasis on the parallels and differences between the three well-studied model systems, M. musculus, D. melanogaster and C. elegans.

Keywords: X chromosomes; mechanisms.

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Conflict of interest statement

Competing Interests: The author has declared that no competing interest exists.

Figures

Figure 1
Figure 1
Genomic changes that lead to dosage differences. A) Duplication or deletion of different sizes of chromosomal segments are depicted. B) In a diploid species with X chromosomes, males contain a single X chromosome compared to two copies of each autosome. In species where Y chromosome does not contain many X-linked gene alleles (e.g. human), or in species where Y chromosome is nonexistent (e.g. C. elegans), X is monosomic in males.
Figure 2
Figure 2
Evolution of the X chromosomes, and Ohno's hypothesis. A) It is hypothesized that the sex chromosomes evolved by formation of a sex locus on the Y chromosome followed by suppressed recombination around this locus. With time, Y chromosome slowly degenerated. B) Upper panel: Ohno hypothesized that due to Y chromosome degeneration, the remaining alleles on the X chromosome became potentially haploinsufficient. To compensate for this, the alleles on the X chromosome were transcriptionally upregulated. Lower panel: It was also hypothesized that the upregulation of X alleles were not limited to males, and also occurred in females. This caused a potential overtranscription of the X-linked genes in females, therefore female-specific downregulation occurred. C) To test if X-upregulation occurred, one should compare ancestral (autosomal) and present level of X-linked gene expression. Since this is not possible, assuming that the function and expression of 1:1 orthologs are conserved, one can compare expression of 1:1 orthologs that are differentially located on X or autosomes. Recent studies on Ohno's hypothesis suggest that X-uprgeulation is only one of the several mechanisms of dealing with potential X haploinsufficieny, and not all genes were upregulated (see text).
Figure 3
Figure 3
X chromosome dosage compensation strategies in mammals, flies and worms. In flies, a male-specific dosage compensation complex increases X chromosome transcription in males, compensating both for potential monosomy of the X with respect to autosomes, and for X chromosome dosage difference between XY males and XX females. In mammals and in worms, X was hypothesized to be upregulated in males to counteract potential X monosomy in XO males. In females, upregulation of the X was counteracted by female-specific dosage compensation mechanisms. In mammals, X inactivation silences one of the X chromosomes in XX females to equalize X dosage between XY males and XX females. In worms both X chromosomes are downregulated by a factor of two in hermaphrodites to equalize X chromosome dosage between XX hermaphrodites and XO males. Note that X-upregulation did not apply to all genes (see Ohno's hypothesis section in the text).
Figure 4
Figure 4
Recruitment of the dosage compensation complexes in mammals, flies and worms. A) In mouse, one of the homologs is inactivated (Xi) and the other remains active (Xa). X inactivation is initiated randomly by monoallelic expression of a long noncoding RNA named Xist from the X chromosome that is destined to be inactivated. Xist may interact and recruit multiple proteins to the X. In flies, male specific dosage compensation complex (MSL) is assembled with either of the two noncoding RNAs named roX1 and roX2 at their loci. MSL complex is recruited to the X chromosome at a number of chromatin entry sites (CES). In worms, the hermaphrodite specific dosage compensation complex (DCC) is initially recruited to the X chromosome at a number of recruitment sites on the X (rex). B) Left panel: The core of the worm DCC is a 5-subunit condensin complex that shares 4/5 subunits with the canonical condensin I. At least five additional proteins interact with the condensin core and have a role in dosage compensation. A 12-bp motif (MEX) is enriched at the DCC recruitment sites on the X, and is shown below. Right panel: Subunits of the MSL complex and the structural noncoding RNA (roX) is shown in grey. A DNA sequence motif called MRE is enriched under the MSL recruitment sites on the X chromosome. CLAMP is required for MSL recruitment to the X. C) Both MEX and MRE are enriched on their respective X chromosomes, but there are many motifs present on the autosomes that are not bound by the dosage compensation complexes.
Figure 5
Figure 5
Spreading of the dosage compensation complexes in mammals, flies and worms. A) In mammals, Xist spreads initially to a number of loci, and then spreads along the rest of the X chromosome, binding at genes that are silenced. In flies, after recruitment to the CES sites, MSL complex spreads onto the X chromosome, preferentially accumulating towards the 3' end of transcribed regions of active genes. In worms, after recruitment to the rex sites, the DCC spreads onto the X chromosome, preferentially accumulating at a subset of active gene promoters and enhancers. B) In mammals, recent studies suggest that Xist spreading along the X chromosome may be aided by three-dimensional interactions between distant loci.
Figure 6
Figure 6
The effect of the dosage compensation complex on the X chromosome chromatin structure. In all three cases, a number of histone modifications are increased and some modifications are decreased on the X chromosome. While X inactivation silences most of X-linked genes, in C. elegans and D. melanogaster, transcription from the X chromosome is regulated by an average of two-fold.
Figure 7
Figure 7
The link between dosage compensation and development. A) Dosage compensation is integrated into the transcriptional networks that are required for proper development. In worms and flies, sex determination pathways control sex-specific recruitment of the dosage compensation complexes to the X chromosome. B) Recent studies suggest that transcriptional pathways that promote multipotency repress X inactivation, which promotes differentiation.
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References

    1. Torres EM, Williams BR, Amon A. Aneuploidy: cells losing their balance. Genetics. 2008;179:737–46. doi:10.1534/genetics.108.090878. - PMC - PubMed
    1. Tang YC, Amon A. Gene copy-number alterations: a cost-benefit analysis. Cell. 2013;152:394–405. doi:10.1016/j.cell.2012.11.043. - PMC - PubMed
    1. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007;317:916–24. doi:10.1126/science.1142210. - PubMed
    1. Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L. et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature. 2010;468:321–5. doi:10.1038/nature09529. - PMC - PubMed
    1. Huettel B, Kreil DP, Matzke M, Matzke AJ. Effects of aneuploidy on genome structure, expression, and interphase organization in Arabidopsis thaliana. PLoS genetics. 2008;4:e1000226.. doi:10.1371/journal.pgen.1000226. - PMC - PubMed

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