Retrotransposons, in the form of LTR and non-LTR elements, constitute >20% of the sequences in mammalian genomes. These elements pose a burden to genome stability, as their mobilization facilitates insertional activation/inactivation, and promotes recombination between non-homologous loci, leading to chromosomal deletions and translocations. Retrotranspositions have resulted in genetic disease in humans, e.g., breast cancer, colon cancer, and muscular dystrophy. It is clear that retrotranspositions are mutagenic, ongoing events that alter mammalian genomes. Multicellular organisms utilize methylation of cytosine bases, siRNA, and posttranslational modifications of histones to stabilize retrotransposons and heterochromatin, to silence genes, and to prevent mobilization of transposons. We have demonstrated that histones are modified by covalent binding of the vitamin biotin. Here we provide the first evidence of biotin-dependent silencing of retrotransposons, suggesting that this mechanism may function in genome stability by decreasing the mobility of endogenous elements. Long-term objective: To identify pathways by which vitamin-dependent chromatin remodeling maintains genome stability.
Specific aims : (1) Aim 1 studies will test the hypothesis that particular species of biotinylated histones are marks for retrotransposons in mammalian genomes. Here, we will identify novel histone biotinylation marks in chromatin associated with distinct regions in LTRs and LINEs in human cells and agouti mice. (2) Aim 2 studies will test the hypothesis that the level of histone biotinylation at retrotransposons depends on biotin supply in mammalian cells. We will also test the hypotheses that some regions in retrotransposons are more susceptible to biotin depletion than other regions, and that some biotinylation sites in histones are more susceptible to biotin depletion than other sites. Finally, we will test the hypothesis that biotin depletion causes increased breast cancer incidence in a unique, novel mouse model containing three integrated copies of the mouse mammary tumor virus. (3) Aim 3 studies will test the hypothesis that biotin deficiency increases transcription, translation, and mobilization of retrotransposons, decreasing genome stability in human cells.
Biotin deficiency is prevalent among Americans, e.g., moderate biotin deficiency has been observed in up to 50% of pregnant women. This proposal lays the groundwork for decreasing the incidence of retrotransposon-associated diseases in groups at risk for developing biotin deficiency such as pregnant women and their fetuses.
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