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首页> 外文期刊>BMC Medical Genomics >Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C
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Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

机译：组蛋白H3赖氨酸4去甲基酶KDM5C突变的个体中DNA甲基化的多位点丢失

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Background A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment. Results Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5 , SCMH1 , CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D . In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP . Conclusions We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.
机译：背景技术许多神经发育综合症是由编码通常在表观遗传调控中起作用的蛋白质的基因突变引起的。在这些疾病中发生的表观遗传学改变的鉴定可以阐明与神经发育相关的分子途径。结果使用全基因组方法，与年龄/性别匹配的对照组相比，我们鉴定了具有智力障碍的男性血液中具有显着DNA甲基化损失的基因，以及X连锁的KDM5C基因中的突变，该基因编码组蛋白H3赖氨酸4脱甲基酶。 。在这种个体中DNA甲基化的丧失与DNA甲基化和H3赖氨酸4甲基化之间的已知相互作用是一致的。此外，在超过900个人群对照中未观察到三个最高候选基因FBXL5，SCMH1，CACYBP的启动子的DNA甲基化损失。我们还发现，血液中这三个基因的DNA甲基化与KDM5C的剂量及其Y连锁同源KDM5D有关。另外，在FBXL5和CACYBP处观察到来自对照雄性和雌性的脑样本中平行的性别特异性DNA甲基化谱。结论我们首次在患者样品中鉴定出表观遗传学改变，该患者样品携带与组蛋白修饰调控基因相关的突变。这些数据支持了DNA甲基化和H3赖氨酸4甲基化在功能上相互依赖的概念。数据为智力障碍的分子发病机理提供了新的见解。此外，我们的数据表明，血液中鉴定出的一些DNA甲基化标记可以充当大脑表观遗传状态的生物标记。

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