Environmental stability of heritable chromatin states

描述：(改编自申请人的摘要)：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结构和可获得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和亲本印记也通过减数分裂在染色质内的特定DNA区域施加可遗传的标记。显然，如果这些标记或印记过早丢失，或者施加不当，那么基因表达水平的控制可能会受到不利影响。显然，如果关键的早期生长调节基因或重要的细胞周期控制基因发生这种情况，严重的儿童疾病或癌症可能就是结果之一。事实上，已经有人提出，某些已知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的丧失(例如，在肿瘤抑制基因中)。在这项提案中，目标是测试各种潜在的环境危险化学污染物，看看它们是否有能力通过在被调查的遗传位点施加改变的染色质状态来遗传地改变基因表达。在这些实验中，遗传上易驯化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，在一系列环境因素存在的情况下，这些现象很容易受到详细的分析。此外，在这个器官中存在一套高度复杂的遗传工具，包括高效的转座子动员和可控的突变和有丝分裂重组程序，这将使我们能够安装一个旨在识别与环境因子合作或介导环境因子与染色体底物相互作用的基因的屏幕。

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.