Environmental stability of heritable chromatin states

可遗传染色质状态的环境稳定性

• 批准号: 6518217
• 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 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518217
• 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：（改编自申请人摘要）：在完成基因表达调控的机制中，在染色质结构水平上控制DNA结构和可及性的机制越来越被认为是至关重要的。在这方面特别令人着迷的是印记现象，即体细胞或生殖细胞衍生的机制通过许多有丝分裂在染色质内的特定DNA区域施加可遗传标记，在亲代印记的情况下，也通过减数分裂。很明显，如果这些标记或印记过早地丢失，或者不适当地施加，那么基因表达水平的控制就会受到不利影响。显然，如果这种情况发生在关键的早期生长调节基因，或重要的细胞周期控制基因上，严重的儿童疾病或癌症状况可能是一个结果。事实上，有人认为，某些已知会致癌但没有明显致突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（例如肿瘤抑制基因）的丧失。在这个提议的目标是测试各种这样的潜在环境危险的化学污染物的能力，遗传性地改变基因表达通过施加改变染色质状态的遗传位点被调查。在这些实验中，遗传上易于处理的真核生物，黑腹果蝇，将作为一个非常合适的模型，因为在这个系统中描述了许多表观遗传现象，这些现象可以很容易地在一系列环境因子的存在下进行详细分析。此外，在这个器官中存在一套高度复杂的遗传工具，包括有效的转座子动员和可控的突变和有丝分裂重组程序，将允许安装一个屏幕，旨在识别与环境因子与染色体底物合作或介导相互作用的基因。