Derivation of consensus inactivation status for X-linked genes from genome-wide studies

Abstract

BackgroundX chromosome inactivation is the epigenetic silencing of the majority of the genes on one of the X chromosomes in XX therian mammals. In humans, approximately 15 % of genes consistently escape from this inactivation and another 15 % of genes vary between individuals or tissues in whether they are subject to, or escape from, inactivation. Multiple studies have provided inactivation status calls for a large subset of the genes on the X chromosome; however, these studies vary in which genes they were able to make calls for and in some cases which call they give a specific gene.MethodsThis analysis aggregated three published studies that have examined X chromosome inactivation status of genes across the X chromosome, generating consensus calls and identifying discordancies. The impact of expression level and chromosomal location on X chromosome inactivation status was also assessed.ResultsOverall, we assigned a consensus XCI status 639 genes, including 78 % of protein-coding genes expressed outside of the testes, with a lower frequency for non-coding RNA and testis-specific genes. Study-specific discordancies suggest that there may be instability of XCI during cell culture and also highlight study-specific variations in call type. We observe an enrichment of discordant genes at boundaries between genes subject to and escaping from inactivation.ConclusionsThis study has compiled a comprehensive list of X-chromosome inactivation statuses for genes and also discovered some biases which will help guide future studies examining X-chromosome inactivation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-015-0053-7) contains supplementary material, which is available to authorized users.

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

“…Many escapees are distinguishable from their X-inactivated counterparts by promoter and gene-body DNA methylation signatures [38 -40]. X-chromosome-wide comparison of CpG island promoter methylation has particularly high concordance with previous assessments of XCI status [28], although approximately 10% of X genes with CpG islands have intermediate methylation levels precluding XCI status assignment [38]. Open chromatin assessed by the Assay for Transposase-Accessible Chromatin (ATAC)-seq, has also been used to determine XCI status and detects gender differences at escapees with higher power and accuracy using fewer samples than expression microarrays [41].…”

“…While each XCI profiling strategy has advantages and disadvantages, results are largely complementary [28] and a clear picture of the human XCI landscape has emerged and continues to be refined. To overcome mosaicism, early studies to evaluate XCI status in humans used cells from female carriers of X-linked disorders and assayed protein variants in clonal cell populations or enzyme activity from human inactive X chromosomes segregated in rodent -human somatic cell hybrids [29,30].…”

“…To date, the XCI status for more than 680 genes on the human X chromosome has been catalogued in up to 29 tissues (figure 1a). This includes almost 80% of protein coding genes [28], not considering the multi-copy testis-expressed genes that have accumulated on the X. Importantly, a comparison indicates that discordant XCI classification between studies is relatively rare (estimated at approximately 10%) [28].…”

“…This includes almost 80% of protein coding genes [28], not considering the multi-copy testis-expressed genes that have accumulated on the X. Importantly, a comparison indicates that discordant XCI classification between studies is relatively rare (estimated at approximately 10%) [28]. Differing XCI assignments can reflect differences in the samples assayed, as escape is probably increased in cultured cells and hybrids compared with primary tissues [28,44], but may also reflect differential assay sensitivity and/or criteria to detect and classify low, but potentially biologically significant, expression from the inactive X (figure 1b).…”

X-Chromosome Inactivation and Escape from X Inactivation in Mouse

“…This study showed that expression of an escape gene on the inactive X chromosome is highly variable, ranging from a few percent to 50%, and rarely reaching 75% of the expression on the active X allele [2]. In addition, one should keep in mind that escape from XCI varies between cell types, tissues and individuals both in human and mouse [18, 19]. …”