Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation
Abstract Background X-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 modif...
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Epigenetics & Chromatin |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13072-021-00404-9 |
| _version_ | 1819081664119177216 |
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| author | Bradley P. Balaton Carolyn J. Brown |
| author_facet | Bradley P. Balaton Carolyn J. Brown |
| author_sort | Bradley P. Balaton |
| collection | DOAJ |
| description | Abstract Background X-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. Results Using 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. Conclusion The 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. |
| first_indexed | 2024-12-21T20:04:22Z |
| format | Article |
| id | doaj.art-3e05d331aa0e401b87666ce59f5848fa |
| institution | Directory Open Access Journal |
| issn | 1756-8935 |
| language | English |
| last_indexed | 2024-12-21T20:04:22Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics & Chromatin |
| spelling | doaj.art-3e05d331aa0e401b87666ce59f5848fa2022-12-21T18:51:53ZengBMCEpigenetics & Chromatin1756-89352021-06-0114112210.1186/s13072-021-00404-9Contribution of genetic and epigenetic changes to escape from X-chromosome inactivationBradley P. Balaton0Carolyn J. Brown1Department of Medical Genetics, The University of British ColumbiaDepartment of Medical Genetics, The University of British ColumbiaAbstract Background X-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. Results Using 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. Conclusion The 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.https://doi.org/10.1186/s13072-021-00404-9X-chromosome inactivationEpigeneticsDNA methylationHistone marksH3K27me3H3K4me3 |
| spellingShingle | Bradley P. Balaton Carolyn J. Brown Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation Epigenetics & Chromatin X-chromosome inactivation Epigenetics DNA methylation Histone marks H3K27me3 H3K4me3 |
| title | Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation |
| title_full | Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation |
| title_fullStr | Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation |
| title_full_unstemmed | Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation |
| title_short | Contribution of genetic and epigenetic changes to escape from X-chromosome inactivation |
| title_sort | contribution of genetic and epigenetic changes to escape from x chromosome inactivation |
| topic | X-chromosome inactivation Epigenetics DNA methylation Histone marks H3K27me3 H3K4me3 |
| url | https://doi.org/10.1186/s13072-021-00404-9 |
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