Epigenetic effects of biotin on activation of endogenous viral sequences

描述（由申请人提供）： 人类基因组包含许多内源性逆转录病毒（HERV）元件。这些元件的表达与癌症、自身免疫、胎盘发育受损和损害基因组稳定性的重组事件相关。表观遗传事件，如DNA甲基化和组蛋白修饰在抑制HERV元件的转录中起着至关重要的作用。最近，一种新的修饰的组蛋白，这是由全羧化酶合成酶（HCS）介导的已被确定：维生素生物素的不同的赖氨酸残基在组蛋白H2 A，H3和H4的结合。具体而言，这里已经证明K8-生物素化H4（K8 Bio H4）和K12-生物素化H4（K12 Bio H4）与基因沉默和异染色质结构相关。重要的是，生物素化组蛋白的丰度取决于膳食生物素供应。可以说，饮食是一个环境因素，可以很容易地操纵影响表观遗传事件，促进人类健康。长期目标是确定表观遗传机制，通过该机制，饮食中生物素摄取的变化改变HERV的表达。具体目的是检验以下假设：1）K8 Bio H4和K12 Bio H4与人类基因组中HERV启动子序列处的甲基化DNA共定位。此外，该目的将检验HCS的敲低与组蛋白的生物素化降低相关的假设，介导病毒元件的去阻遏;和2）膳食生物素缺乏降低HERV启动子基因座处K8 Bio H4和K12 Bio H4的丰度。以此为目的的研究将检验生物素缺乏与HERV元件的去阻遏相关的想法，促进人类细胞中的异常生长、转化和基因组不稳定性。生物素缺乏和补充在美国相当普遍。这里提出的研究调查了一种新颖独特的机制，通过这种机制，维生素生物素的饮食供应调节对HERV沉默至关重要的表观遗传事件。这些研究有可能确定操纵环境因素“饮食”增加基因组稳定性和降低癌症风险的方法。

DESCRIPTION (provided by applicant): The human genome contains numerous endogenous retroviral (HERV) elements. Expression of these elements is associated with cancer, autoimmunity, impaired placental development, and recombination events that impair genomic stability. Epigenetic events such as DNA methylation and histone modifications play crucial roles in repressing transcription of HERV elements. Recently, a novel modification of histones that is mediated by holocarboxylase synthetase (HCS) has been identified: binding of the vitamin biotin to distinct lysine residues in histones H2A, H3, and H4. Specifically, it has been demonstrated here that K8- biotinylated H4 (K8Bio H4) and K12-biotinylated H4 (K12Bio H4) are associated with gene silencing and heterochromatin structures. Importantly, the abundance of biotinylated histones depends on dietary biotin supply. Arguably, diet is an environmental factor that can be easily manipulated to affect epigenetic events that promote human health. The long-term objective is to identify epigenetic mechanisms through which changes in the dietary uptake of biotin alter expression of HERV. The specific aims are to test the hypothesis that: 1) K8Bio H4 and K12Bio H4 co-localize with methylated DNA at HERV promoter sequences in the human genome. Further, this aim will test the hypothesis that knockdown of HCS is associated with decreased biotinylation of histones, mediating de-repression of viral elements; and 2) Dietary biotin deficiency decreases the abundance of K8Bio H4 and K12Bio H4 at HERV promoter loci. Studies with this aim will test the idea that biotin deficiency is associated de-repression of HERV elements, promoting abnormal growth, transformation, and genomic instability in human cells. Both biotin deficiency and supplementation are fairly common in the U.S. The research proposed here investigates a novel and unique mechanism by which dietary supply of the vitamin biotin modulates epigenetic events that are crucial for HERV silencing. These studies are likely to identify means by which manipulation of the environmental factor "diet" increases genomic stability and decreases cancer risk.