Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation.
Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation.
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DOI：
10.1093/hmg/ddu564
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发表时间：
2015-03-15
影响因子：
3.5
通讯作者：
Brown CJ
中科院分区：
文献类型：
--
作者：
Cotton AM;Price EM;Jones MJ;Balaton BP;Kobor MS;Brown CJ
X染色体失活（XCI）通过沉默女性X染色体上的大多数基因来实现男性和女性之间的剂量补偿。因此，女性X染色体提供了一个独特的机会，研究常染色质和异染色质的等位基因区域内相同的核环境。我们使用Illumina Infinium Human Methylation 450 BeadChip分析了1800多名女性样本，研究了X染色体上基因的DNA甲基化（DNAm）与CpG密度、转录活性和染色质状态的相互作用。DNAm用于预测27种组织中63个新转录起始位点（TSS）的失活状态。有高一致性的失活状态的组织，与62%的TSS受XCI在所有27个组织检查，而9%的逃脱XCI在所有组织中，其余的显示变量逃脱XCI之间的女性之间的组织子集。女性间和双胞胎的数据支持的模型，主要是顺式作用的影响失活状态。相对于活性X，来自非活性X的表达水平与女性启动子DNAm的量相关，阈值为30%，超过该阈值，基因始终受到失活。在基因内和基因间区域，不活跃的X表现出比活跃的X更低的DNAm，而不是在逃避失活的基因中。我们对逃避X失活的基因的分类为疾病的性别特异性差异提供了候选者。
X-chromosome inactivation (XCI) achieves dosage compensation between males and females through the silencing of the majority of genes on one of the female X chromosomes. Thus, the female X chromosomes provide a unique opportunity to study euchromatin and heterochromatin of allelic regions within the same nuclear environment. We examined the interplay of DNA methylation (DNAm) with CpG density, transcriptional activity and chromatin state at genes on the X chromosome using over 1800 female samples analysed with the Illumina Infinium Human Methylation450 BeadChip. DNAm was used to predict an inactivation status for 63 novel transcription start sites (TSSs) across 27 tissues. There was high concordance of inactivation status across tissues, with 62% of TSSs subject to XCI in all 27 tissues examined, whereas 9% escaped from XCI in all tissues, and the remainder showed variable escape from XCI between females in subsets of tissues. Inter-female and twin data supported a model of predominately cis-acting influences on inactivation status. The level of expression from the inactive X relative to the active X correlated with the amount of female promoter DNAm to a threshold of ∼30%, beyond which genes were consistently subject to inactivation. The inactive X showed lower DNAm than the active X at intragenic and intergenic regions for genes subject to XCI, but not at genes that escape from inactivation. Our categorization of genes that escape from X inactivation provides candidates for sex-specific differences in disease.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
12.3
作者：
Lou S;Lee HM;Qin H;Li JW;Gao Z;Liu X;Chan LL;Kl Lam V;So WY;Wang Y;Lok S;Wang J;Ma RC;Tsui SK;Chan JC;Chan TF;Yip KY
通讯作者：
Yip KY
影响因子：
3.7
作者：
Bocklandt S;Lin W;Sehl ME;Sánchez FJ;Sinsheimer JS;Horvath S;Vilain E
通讯作者：
Vilain E
影响因子：
3.5
作者：
Cotton AM;Chen CY;Lam LL;Wasserman WW;Kobor MS;Brown CJ
通讯作者：
Brown CJ
影响因子：
12.3
作者：
Lokk K;Modhukur V;Rajashekar B;Märtens K;Mägi R;Kolde R;Koltšina M;Nilsson TK;Vilo J;Salumets A;Tõnisson N
通讯作者：
Tõnisson N