Department of Medical Genetics, The University of British Columbia, Vancouver, Canada.
Epigenetics Chromatin. 2021 Jun 29;14(1):30. doi: 10.1186/s13072-021-00404-9.
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.
X 染色体失活（XCI）是 XX 真哺乳类动物中两条 X 染色体之一的表观遗传失活。失活的 X 染色体是多个沉默途径共同作用的结果，这些途径会导致染色质发生变化，包括 DNA 甲基化和组蛋白修饰。然而，超过 15%的基因逃避或可变地逃避失活，并继续从其他失活的 X 染色体表达。在已经研究过的程度上，表观遗传标记与这种表达相关。
我们使用公开可用的数据，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，失活 X 上富含异染色质标记，而耗竭 euchromatic 标记。逃避 XCI 的基因在活性和失活 X 之间更为相似。使用特定于样本的 XCI 状态调用，我们发现一些标记与可变 XCI 状态显著不同，但哪些标记具有显著差异在基因之间并不一致。从这些表观遗传标记中训练的预测 XCI 状态的模型对逃避 XCI 的基因获得了超过 75%的准确性，对受 XCI 影响的基因获得了超过 90%的准确性。该模型为没有等位基因差异或其他方法所需的 CpG 岛的基因进行了新的 XCI 状态调用。在一个可变逃避基因的域中检查这些调用，我们看到 XCI 状态在单个基因之间变化，而不是在域级别变化。最后，我们将 XCI 状态调用与遗传多态性进行了比较，发现多个与可变逃避基因的 XCI 状态变化相关的位点，但没有一个单独足以诱导 XCI 状态变化。
失活 X 染色体表达的控制是多方面的，但最终在个体基因水平上受到调节，具有可检测但有限的远距离多态性影响。在失活的 X 染色体上，在沉默的基因中， euchromatic 标记被耗尽，而 heterochromatic 标记被富集。逃避失活的基因显示出异染色质标记的富集程度降低，而 H3K27ac 的耗尽程度降低。结合所有检查过的标记可以提高 XCI 状态预测的准确性，特别是对于没有 CpG 岛或多态性的基因，因为没有一个单一的特征是沉默或表达基因的一致特征。
