Defining the molecular and cellular mechanism of epigenetic transcriptional memory

 描述(由申请人提供)：了解控制细胞对环境信号转录反应的表观遗传机制的分子基础，对于了解环境、衰老和生活方式如何影响生理学至关重要。我的实验室发现了一种进化保守的表观遗传转录记忆机制，它涉及基因与核孔蛋白的相互作用(8-10)。使用酵母中的INO1基因和HeLa细胞中干扰素γ诱导的基因作为转录记忆的模型，我们发现以前表达的基因与核孔蛋白相互作用了4-7代，这导致了这些基因启动子中染色质结构的改变。这使得RNA聚合酶II可以与这些启动子结合，使它们能够重新激活。我们现在已经发现，转录记忆调控的基因范围包括酵母中数十个利用相同系统的应激诱导基因。因此，转录记忆是一种普遍的、古老的和保守的机制，细胞可以通过它整合以前的经验来影响未来的生理。这项工作的目标是确定控制酵母和人类细胞中转录记忆的建立和遗传的分子机制。

 DESCRIPTION (provided by applicant): Understanding the molecular basis of epigenetic mechanisms that control the transcriptional response of cells to environmental signals is essential to understand how environment, aging and lifestyle impact physiology. My lab has discovered an evolutionarily conserved mechanism of epigenetically inherited transcriptional memory that involves the interaction of genes with nuclear pore proteins (8-10). Using both the INO1 gene from yeast and interferon γ-inducible genes in HeLa cells as models for transcriptional memory, we find that previously expressed genes interact with nuclear pore proteins for 4- 7 generations and this leads to an altered chromatin structure in the promoters of these genes. This allows RNA polymerase II to bind to these promoters, poising them for re-activation. We have now find that the scope of genes regulated by transcriptional memory includes dozens of stress-induced genes in yeast that utilize the same system. Therefore, transcriptional memory is a universal, ancient and conserved mechanism by which cells can integrate previous experience to affect future physiology. The goals of this work are to determine the molecular mechanisms that control establishment and inheritance of transcriptional memory in yeast and human cells.