Cellular memory of developmental history in C elegans

描述（由申请人提供）：动物的环境和发育经历会导致基因表达的表观遗传编程，从而导致行为和生理的改变。秀丽隐杆线虫为研究基因表达长期可塑性的分子机制提供了一个简单的系统。在第一个幼虫阶段，暴露于不利的环境线索会触发一个关键的发育决定，是进入替代动力阶段，还是继续生殖生长。动物在改善的环境条件下，退出生育期，恢复生殖生长。先前的一些报告表明，在经历过死亡阶段的动物和经历过死亡阶段的动物之间，基因表达模式和组织形态可能有所不同，这表明动物对发育和环境历史的细胞记忆有所保留。然而，这种细胞记忆的机制及其后果尚未被探索。由osm-9 TRPV通道基因调控序列驱动的gfp报告基因的表达在成年动物的神经元中发生了改变，这是探索这种细胞记忆形式的机制的一个很好的标记。我的目标是识别和研究神经元基因表达被动物的发育和环境经历改变的分子机制，并探索其行为和生理后果。具体来说，我将：1)探索幼虫阶段的发育经历调节成年动物中osm-9 TRPV通道等基因表达的机制，2)确定受类似机制调节的其他基因，以及3)确定基因表达的表观遗传编程所需的分子途径。这项工作将确定秀丽隐杆线虫细胞记忆的机制和目标。表观遗传编程在包括哺乳动物在内的许多物种中都有描述，并已被证明在分化和疾病中发挥关键作用。表观遗传调控的分子机制在物种间高度保守；因此，了解这种基因表达机制将与人类发育和疾病高度相关。概述：目标是了解由生物体先前的发育和环境经验导致的基因调控机制。这项工作的结果将使人们更好地理解早期经历对行为和生理长期变化的重要性。

DESCRIPTION (provided by applicant): The environmental and developmental experience of an animal can result in epigenetic programming of gene expression, resulting in altered behaviors and physiology. C. elegans provides a simple system in which to investigate the molecular mechanisms underlying long-term plasticity in gene expression. During the first larval stage, exposure to adverse environmental cues triggers a critical developmental decision between entry into the alternative dauer stage, or continued reproductive growth. Animals exit the dauer stage and resume reproductive growth under improved environmental conditions. A few previous reports have suggested that gene expression patterns and tissue morphology may differ between post-dauer animals and those that have bypassed the dauer stage, suggesting retention of a cellular memory of the animal's developmental and environmental history. However, the mechanisms of this cellular memory and its consequences have not been explored. Expression of the gfp reporter gene driven by the osm-9 TRPV channel gene regulatory sequences is altered in neurons of adult animals that have passed through the dauer stage, serving as an excellent marker to explore the mechanisms underlying this form of cellular memory. My goal is to identify and investigate the molecular mechanisms by which neuronal gene expression is altered by an animal's developmental and environmental experience, and to explore its behavioral and physiological consequences. Specifically, I will: 1) Explore the mechanisms by which developmental experience in larval stages regulates the expression of genes such as the osm-9 TRPV channel in adult animals, 2) Identify additional genes that are regulated by similar mechanisms, and 3) Identify the molecular pathways required for this epigenetic programming of gene expression. This work will identify the mechanisms and targets of cellular memory in C. elegans. Epigenetic programming has been described in numerous species, including mammals, and has been shown to play a critical role in differentiation and disease. The molecular mechanisms of epigenetic regulation are highly conserved across species; thus, understanding this mechanism of gene expression will be highly relevant to human development and disease. Lay summary: The goal is to understand the mechanisms of gene regulation resulting from an organism's prior developmental and environmental experience. The results of this work will allow greater understanding of the importance of early experience in long-term changes in behavior and physiology.