Environmental stability of heritable chromatin states

可遗传染色质状态的环境稳定性

• 批准号: 6321519
• 负责人: IAIN L CARTWRIGHT
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6321519
• 关键词: Drosophilidae; cell cycle; chromatin; environmental contamination; gene environment interaction; gene expression; hazardous substances; mutagen testing; mutagens; transposon /insertion element

DESCRIPTION: (Adapted from the Applicant's Abstract): Among the mechanisms by which the regulation of gene expression is accomplished, that which controls the structure and accessibility of the DNA at the level of chromatin structure is increasingly recognized as being critically important. Particularly fascinating in this regard is the phenomenon of imprinting, whereby somatic or germ cell-derived mechanisms impose a heritable mark on particular region of DNA within chromatin through many mitoses and, in the case of parental imprinting, through meiosis as well. It seems clear that if these marks or imprints are either lost prematurely, or else imposed inappropriately, then control of the level of expression of genes can be affected adversely. Clearly if this happens to critical early growth regulatory genes, or to important cell cycle control genes, serious childhood diseases or cancerous conditions could be one result. In fact, it has been suggested that certain environmental chemicals, known to cause cancer but with no overt mutagenic properties, might create a loss of gene expression (e.g. in tumor suppressor genes) by such epigenetic means. In this proposal the goal is to test a variety of such potential environmentally dangerous chemicals contaminants for their ability to heritably alter gene expression via imposition of altered chromatin states at the genetic locus under investigation. In these experiments the genetically tractable eukaryote, Drosophila melanogaster, will serve as a highly appropriate model since there are numerous epigenetic phenomena described in this system that can be readily subjected to detailed analysis in the presence of an array of environmental agents. Moreover, the existence of a highly sophisticated set of genetic tools in this organ, including efficient transposon mobilization and controllable mutagenesis and mitotic recombination procedures, will allow a screen to be mounted that aims to identify genes that co-operate with, or mediate the interaction of, environmental agents with the chromosome substrate.

描述：（根据申请人的摘要进行了改编）：在完成基因表达调控的机制中，控制DNA在染色质结构水平上的结构和可访问性的机制越来越被认为是至关重要的。在这方面尤其令人着迷的是印迹的现象，这些现象通过许多有丝分裂，在染色质中，体细胞或生殖细胞衍生的机制对DNA的特定区域施加了可遗传的标记，并且在父母的印记，也通过减数分裂。似乎很明显，如果这些标记或烙印要么过早丢失，要么不恰当地施加，那么对基因表达水平的控制可能会受到不利影响。显然，如果这发生在临界的早期生长调节基因或重要的细胞周期控制基因，那么严重的儿童疾病或癌症可能是一个结果。实际上，已经提出，某些已知会引起癌症但没有明显的诱变特性的环境化学物质可能会通过这种表观遗传手段造成基因表达（例如在肿瘤抑制基因中）的丧失。在此提案中，目标是测试各种潜在的环境危险化学物质污染物，以便通过在研究的遗传基因座上施加改变的染色质状态来遗传性地改变基因表达。在这些实验中，由于遗传性的真核生物果蝇Melanogaster将作为一个高度适当的模型，因为该系统中描述的许多表观遗传现象可以在存在一系列环境药物的情况下很容易进行详细的分析。此外，在该器官中存在一组高度复杂的遗传工具集，包括有效的转座子动员和可控的诱变和有丝分裂的重组程序，将允许安装屏幕，旨在识别与染色体材料体的环境剂相互作用的基因，或者介导了与染色体的相互作用。