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. 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. 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.

中文翻译：

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遗传和表观遗传变化对逃避 X 染色体失活的贡献

X 染色体失活 (XCI) 是 XX eutherian 哺乳动物中两条 X 染色体之一的表观遗传失活。不活跃的 X 染色体是多种沉默途径的结果，这些途径协同作用以沉积染色质变化，包括 DNA 甲基化和组蛋白修饰。然而，超过 15% 的基因从失活中逃逸或可变地逃逸，并继续从原本不活跃的 X 染色体中表达。在对其进行研究的范围内，表观遗传标记与这种表达相关。使用公开可用的数据，我们将 XCI 状态调用与 DNA 甲基化、H3K4me1、H3K4me3、H3K9me3、H3K27ac、H3K27me3 和 H3K36me3 进行了比较。在受 XCI 影响的基因中，我们发现与活性 X 相比，非活性 X 上的异色标记富集，而常染色标记耗尽。逃逸 XCI 的基因在活动和非活动 X 之间更为相似。使用样本特定的 XCI 状态调用，我们发现一些标记与可变 XCI 状态显着不同，但哪些标记显着在基因之间并不一致。一个经过训练的模型可以从这些表观遗传标记中预测 XCI 状态，对逃逸基因的准确率超过 75%，对受 XCI 影响的基因的准确率超过 90%。该模型对没有其他方法所需的等位基因差异或 CpG 岛的基因进行了新的 XCI 状态调用。检查这些调用跨越一个可变逃逸基因的域，我们看到 XCI 状态在各个基因之间而不是在域水平上有所不同。最后，我们将 XCI 状态调用与遗传多态性进行了比较，发现了多个与 XCI 状态变化相关的位点，这些位点在不同的逃逸基因上，但没有一个单独足以引起 XCI 状态变化。来自失活 X 染色体的表达控制是多方面的，但最终在个体基因水平上受到调控，远距离多态性的影响可检测但有限。在不活跃的 X 上，在沉默的基因处，常染色标记被耗尽，而异染色标记被富集。逃避失活的基因显示出不那么显着的异色标记富集和 H3K27ac 的消耗。结合所有检查的标记改进了 XCI 状态预测，特别是对于没有 CpG 岛或多态性的基因，因为没有单一特征是沉默或表达基因的一致特征。但最终在个体基因水平上受到调控，远距离多态性的影响可检测但有限。在不活跃的 X 上，在沉默的基因处，常染色标记被耗尽，而异染色标记被富集。逃避失活的基因显示出不那么显着的异色标记富集和 H3K27ac 的消耗。结合所有检查的标记改进了 XCI 状态预测，特别是对于没有 CpG 岛或多态性的基因，因为没有单一特征是沉默或表达基因的一致特征。但最终在个体基因水平上受到调控，远距离多态性的影响可检测但有限。在不活跃的 X 上，在沉默的基因处，常染色标记被耗尽，而异染色标记被富集。逃避失活的基因显示出不那么显着的异色标记富集和 H3K27ac 的消耗。结合所有检查的标记改进了 XCI 状态预测，特别是对于没有 CpG 岛或多态性的基因，因为没有单一特征是沉默或表达基因的一致特征。