Environmental stability of heritable chromatin states

产品说明：在完成基因表达调节的机制中，在染色质结构水平上控制DNA的结构和可接近性的机制越来越被认为是至关重要的。在这方面特别吸引人的是印记现象，由此体细胞或生殖细胞衍生的机制通过许多有丝分裂以及在亲本印记的情况下，通过减数分裂在染色质内的DNA的特定区域上施加可遗传的标记。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，那么对基因表达水平的控制就会受到不利影响。显然，如果这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可能是一个结果。事实上，已经有人提出，某些已知会致癌但没有明显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（例如肿瘤抑制基因）的丧失。在本提案中，目标是测试各种此类潜在的环境危险化学品污染物通过在研究的遗传位点施加改变的染色质状态来遗传性地改变基因表达的能力。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，因为有许多表观遗传现象描述在这个系统中，可以很容易地进行详细的分析，在一系列的环境因素的存在下。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诱变和有丝分裂重组程序，将允许安装一个屏幕，目的是确定基因的合作，或介导的相互作用，环境因素与染色体底物。

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.