? 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. ? ? ? ?
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