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A cross-species comparison of escape from X inactivation in Eutheria: implications for evolution of X chromosome inactivation.

ABSTRACT: Sex chromosome dosage compensation in both eutherian and marsupial mammals is achieved by X chromosome inactivation (XCI)--transcriptional repression that silences one of the two X chromosomes in the somatic cells of females. We recently used RNA fluorescent in situ hybridization (FISH) to show, in individual nuclei, that marsupial X inactivation (in the absence of XIST) occurs on a gene-by-gene basis, and that escape from inactivation is stochastic and independent of gene location. In the absence of similar data from fibroblast cell lines of eutherian representatives, a meaningful comparison is lacking. We therefore used RNA-FISH to examine XCI in fibroblast cell lines obtained from three distantly related eutherian model species: African savannah elephant (Loxodonta africana), mouse (Mus musculus) and human (Homo sapiens). We show that, unlike the orthologous marsupial X, inactivation of the X conserved region (XCR) in eutherians generally is complete. Two-colour RNA-FISH on female human, mouse and elephant interphase nuclei showed that XCR loci have monoallelic expression in almost all nuclei. However, we found that many loci located in the evolutionarily distinct recently added region (XAR) displayed reproducible locus-specific frequencies of nuclei with either one or two active X alleles. We propose that marsupial XCI retains features of an ancient incomplete silencing mechanism that was augmented by the evolution of the XIST gene that progressively stabilized the eutherian XCR. In contrast, the recently added region of the eutherian X displays an incomplete inactivation profile similar to that observed on the evolutionarily distinct marsupial X and the independently evolved monotreme X chromosomes.

SUBMITTER: Al Nadaf S

PROVIDER: S-EPMC3260438 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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A cross-species comparison of escape from X inactivation in Eutheria: implications for evolution of X chromosome inactivation.

Al Nadaf Shafagh S Deakin Janine E JE Gilbert Clément C Robinson Terence J TJ Graves Jennifer A M JA Waters Paul D PD Waters Paul D PD

Chromosoma 20110927 1

Sex chromosome dosage compensation in both eutherian and marsupial mammals is achieved by X chromosome inactivation (XCI)--transcriptional repression that silences one of the two X chromosomes in the somatic cells of females. We recently used RNA fluorescent in situ hybridization (FISH) to show, in individual nuclei, that marsupial X inactivation (in the absence of XIST) occurs on a gene-by-gene basis, and that escape from inactivation is stochastic and independent of gene location. In the absen ...[more]

PMID: 21947602

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Project description:BackgroundX-chromosome inactivation (XCI) in eutherian mammals is the epigenetic inactivation of one of the two X chromosomes in XX females in order to compensate for dosage differences with XY males. Not all genes are inactivated, and the proportion escaping from inactivation varies between human and mouse (the two species that have been extensively studied).ResultsWe used DNA methylation to predict the XCI status of X-linked genes with CpG islands across 12 different species: human, chimp, bonobo, gorilla, orangutan, mouse, cow, sheep, goat, pig, horse and dog. We determined the XCI status of 342 CpG islands on average per species, with most species having 80-90% of genes subject to XCI. Mouse was an outlier, with a higher proportion of genes subject to XCI than found in other species. Sixteen genes were found to have discordant X-chromosome inactivation statuses across multiple species, with five of these showing primate-specific escape from XCI. These discordant genes tended to cluster together within the X chromosome, along with genes with similar patterns of escape from XCI. CTCF-binding, ATAC-seq signal and LTR repeats were enriched at genes escaping XCI when compared to genes subject to XCI; however, enrichment was only observed in three or four of the species tested. LINE and DNA repeats showed enrichment around subject genes, but again not in a consistent subset of species.ConclusionsIn this study, we determined XCI status across 12 species, showing mouse to be an outlier with few genes that escape inactivation. Inactivation status is largely conserved across species. The clustering of genes that change XCI status across species implicates a domain-level control. In contrast, the relatively consistent, but not universal correlation of inactivation status with enrichment of repetitive elements or CTCF binding at promoters demonstrates gene-based influences on inactivation state. This study broadens enrichment analysis of regulatory elements to species beyond human and mouse.

Project description:BackgroundX-chromosome inactivation (XCI) is the epigenetic inactivation of one of two X chromosomes in XX eutherian mammals. The inactive X chromosome is the result of multiple silencing pathways that act in concert to deposit chromatin changes, including DNA methylation and histone modifications. Yet over 15% of genes escape or variably escape from inactivation and continue to be expressed from the otherwise inactive X chromosome. To the extent that they have been studied, epigenetic marks correlate with this expression.ResultsUsing publicly available data, we compared XCI status calls with DNA methylation, H3K4me1, H3K4me3, H3K9me3, H3K27ac, H3K27me3 and H3K36me3. At genes subject to XCI we found heterochromatic marks enriched, and euchromatic marks depleted on the inactive X when compared to the active X. Genes escaping XCI were more similar between the active and inactive X. Using sample-specific XCI status calls, we found some marks differed significantly with variable XCI status, but which marks were significant was not consistent between genes. A model trained to predict XCI status from these epigenetic marks obtained over 75% accuracy for genes escaping and over 90% for genes subject to XCI. This model made novel XCI status calls for genes without allelic differences or CpG islands required for other methods. Examining these calls across a domain of variably escaping genes, we saw XCI status vary across individual genes rather than at the domain level. Lastly, we compared XCI status calls to genetic polymorphisms, finding multiple loci associated with XCI status changes at variably escaping genes, but none individually sufficient to induce an XCI status change.ConclusionThe control of expression from the inactive X chromosome is multifaceted, but ultimately regulated at the individual gene level with detectable but limited impact of distant polymorphisms. On the inactive X, at silenced genes euchromatic marks are depleted while heterochromatic marks are enriched. Genes escaping inactivation show a less significant enrichment of heterochromatic marks and depletion of H3K27ac. Combining all examined marks improved XCI status prediction, particularly for genes without CpG islands or polymorphisms, as no single feature is a consistent feature of silenced or expressed genes.

Dataset Information

A cross-species comparison of escape from X inactivation in Eutheria: implications for evolution of X chromosome inactivation.

Publications

A cross-species comparison of escape from X inactivation in Eutheria: implications for evolution of X chromosome inactivation.

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