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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063945-08
Application #
8098143
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2003-04-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2011
Total Cost
$297,158
Indirect Cost
Name
University of Nebraska Lincoln
Department
Miscellaneous
Type
Schools of Education
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
Cordonier, Elizabeth L; Adjam, Riem; Teixeira, Daniel Camara et al. (2015) Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster. J Nutr Biochem 26:1379-84
Liu, Dandan; Zempleni, Janos (2014) Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats. Biochem J 461:477-86
Baier, Scott R; Nguyen, Christopher; Xie, Fang et al. (2014) MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. J Nutr 144:1495-500
Baier, Scott R; Zbasnik, Richard; Schlegel, Vicki et al. (2014) Off-target effects of sulforaphane include the derepression of long terminal repeats through histone acetylation events. J Nutr Biochem 25:665-8
Liu, Dandan; Zempleni, Janos (2014) Low activity of LSD1 elicits a pro-inflammatory gene expression profile in riboflavin-deficient human T Lymphoma Jurkat cells. Genes Nutr 9:422
Zempleni, Janos; Liu, Dandan; Camara, Daniel Teixeira et al. (2014) Novel roles of holocarboxylase synthetase in gene regulation and intermediary metabolism. Nutr Rev 72:369-76
Li, Yong; Malkaram, Sridhar A; Zhou, Jie et al. (2014) Lysine biotinylation and methionine oxidation in the heat shock protein HSP60 synergize in the elimination of reactive oxygen species in human cell cultures. J Nutr Biochem 25:475-82
Sittiwong, Wantanee; Cordonier, Elizabeth L; Zempleni, Janos et al. (2014) ?-Keto and ?-hydroxyphosphonate analogs of biotin-5'-AMP are inhibitors of holocarboxylase synthetase. Bioorg Med Chem Lett 24:5568-5571
Liu, Dandan; Zempleni, Janos (2014) Transcriptional regulation of the albumin gene depends on the removal of histone methylation marks by the FAD-dependent monoamine oxidase lysine-specific demethylase 1 in HepG2 human hepatocarcinoma cells. J Nutr 144:997-1001
Romagnolo, Donato F; Zempleni, Janos; Selmin, Ornella I (2014) Nuclear receptors and epigenetic regulation: opportunities for nutritional targeting and disease prevention. Adv Nutr 5:373-85

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