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Novel histone biotinylation sites and relationships to other epigenetic marks

新型组蛋白生物素化位点及其与其他表观遗传标记的关系

基本信息

批准号：
7895893
负责人：
YIE-HWA CHANG
金额：
$ 25.64万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895893
关键词：
Acetylation Affect American Antibodies Area Binding Biological Biological Process Biotin Biotinylation Cataloging Catalogs Cells Chromatin Chromosome abnormality Chromosomes Chromosomes, Human, Pair 3 DNA Repair Dietary intake Drosophila genus Enzymes Epigenetic Process Event Frequencies Future Gene Expression Regulation Genes Genome Stability Goals Head Heterochromatin Histone H1 Histone H1(s)Histone H2A Histone H3 Histone H4 Histones Human Incidence Incubated K-18 conjugate Laboratories Life Ligase Lysine Maps Mediating Metabolic Methylation Modification Mutation Nutritionist Organism Orthologous Gene Pathway interactions Peptides Play Pregnant Women Protein Isoforms Proteins Public Health Repression Research Research Personnel Retrotransposition Retrotransposon Role SECTM1 gene SU(VAR)3-9 Site Structure Testing Transferase Transgenic Organisms Variant Vitamins base biotin 1 cancer risk fly histone modification holocarboxylase synthetases insight mutant novel overexpression polyclonal antibody public health relevance response tool

项目摘要

DESCRIPTION (provided by applicant): Histones are known to be modified by covalent binding of the vitamin biotin Histone biotinylation is unique among histone modifications in that a metabolic co-factor also functions as a chromatin mark. We have identified ten distinct biotinylation sites in histones H2A, H3, and H4. Additional biotinylation sites are known to exist but have only been tentatively identified. Biotinylation of histones is mediated by holocarboxylase synthetase (HCS) and has important biological functions, e.g., in the repression of retrotransposons, in heterochromatin structures and DNA repair, and in gene regulation. The elucidation of the full spectrum of biological functions of histone biotinylation is currently slowed by our incomplete understanding of histone biotinylation sites, the lack of availability of antibodies to some biotinylation sites, and our lack of understanding of the crosstalk between histone biotinylation and other epigenetic marks. Here, we propose to overcome these obstacles by taking advantage of a unique combination of investigators with expertise in diverse areas of research: a protein biochemist who also is the head of a mass spec laboratory (Chang), a geneticist with extensive expertise in epigenetic mechanisms of gene regulation (Eissenberg), and a nutritionist who discovered histone biotinylation and developed many unique tools in this field (Zempleni). The long-term objective of this project is to identify pathways by which histone biotinylation maintains genome stability. Specific aims: (1) In aim 1, we will identify all naturally occurring biotinylation sites in all histones and variants in living cells by using LC/MS/MS. In addition, we will generate antibodies to novel biotinylation sites. These antibodies will be essential for use in future studies to determine the biological importance of histone biotinylation. (2) In aim 2 we will test the hypothesis that biotinylation co-exists with other modification marks on the same histone molecule in humans. We will generate antibodies to selected examples of histones with multiple modifications. First insights into biological functions will be generated by mapping these modified histone isoforms in Drosophila polytene chromosomes. (3) Ongoing projects in our laboratories suggest that HCS interacts with H3 K9-methyl transferases and that K12-biotinylated histone H4 co-localizes with K9- dimethylated histone H3. Here we will test the hypothesis that HCS knockdown in human cells and flies decreases the abundance of K9Me3H3 at selected loci, and increases the abundance of K4Me3H3 at these loci. We will also test the hypothesis that biotinylation of histones decreases in response to knockdown, mutation, and/or overexpression of K9-methyl transferases. Most of these mutant and transgenic organisms are in our laboratories or freely available. PUBLIC HEALTH RELEVANCE: Biotinylation of histones is a unique epigenetic mark because it depends on the dietary intake of the essential vitamin biotin. Biotin deficiency is prevalent among Americans, and moderate biotin deficiency has been observed in up to 50% of pregnant women. Previous studies suggest that biotinylation of histones plays a critical role in the repression of retrotransposons, thereby decreasing the incidence of retrotranspositions, chromosomal abnormalities, and probably cancer risk.

描述（由申请人提供）：