Epigenetics of Melanoma Metastasis

摘要 恶性黑色素瘤是一种高度侵袭性的疾病，死亡率高得惊人。尽管我们有 对黑色素瘤的遗传决定因素有了实质性的了解，我们对 黑色素瘤转移的表观遗传学机制。因此，这项建议旨在确定表观遗传学 修饰和参与转移过程的因素，并了解它们如何传递转移 对癌细胞有潜在的作用。长期目标是能够识别新的药物靶点并开发诊断 化验。在我之前的培训中，我在研究表观遗传机制方面积累了一些经验 在疾病发展和结肠癌初期。我热衷于将这些经验应用于解决这个问题 使用黑色素瘤系统的重要问题。中国实验室在利用基因组数据集和大规模应用方面的专业知识 了解黑色素瘤转移的筛查和多种黑色素瘤小鼠模型的可用性为我提供了一个 完美的环境来解决我感兴趣的科学问题。在这项提议中，我的目的是理解 利用新的表观基因组研究黑色素瘤细胞促转移特性的表观遗传学机制 方法，强大的活体屏幕和小鼠模型。在目标1中，我将阐明亲和力的机制- RNF2的转移作用，并评估其作为药物靶点的潜力。在目标2中，我将确定表观基因组 努力识别受影响的细胞系统的非转移细胞和促进转移细胞的情况 通过转移性表观遗传学改变。在目标3中，我将采取不偏不倚的方法，在体内大规模使用 在小鼠中进行筛选，以确定表观遗传转移的促进者和抑制者。“命中”的机制 从这个屏幕开始，将研究目标1和目标2中用于RNF2的方法。总的来说，我在表观基因组学方法方面的培训， 鼠标建模和大型活体屏幕将磨练我的科学技能，为我成功地 独立的事业。在我的独立阶段，我将确定新的转移抑制因子的机制 以及由建议筛选确定的推广者。此外，我将建立老鼠和斑马鱼模型来评估 这些基因作为药物靶点的能力。最后，我希望通过这些研究来确定新的药物靶点 表观遗传作用和可能的表观遗传标记(在特定的基因组座位上)，用于设计新的诊断 方法：研究方法。

Summary Malignant melanoma is a highly aggressive disease with alarmingly high mortality rates. Although we have gained substantial understanding of genetic determinants of the melanoma, we have very limited knowledge of epigenetic mechanisms underlying melanoma metastasis. Therefore, this proposal aims to identify epigenetic modifications and factors involved in the process of metastasis and understand how they impart metastatic potential to cancer cells. The long term-goal is to be able to identify novel drug targets and develop diagnostic assays. During my previous training, I have gained some experience in studying epigenetic mechanisms during development and colon cancer initiation. I am keen to apply some of this experience in addressing this vital question using melanoma system. The Chin lab's expertise in utilizing genomic datasets and large scale screens to understand metastasis and the availability of multiple mouse models of melanoma provides me a perfect environment to address the scientific question of my interest. In this proposal I aim to understand epigenetic mechanisms underlying pro-metastatic properties of melanoma cells utilizing new epigenomic methods, powerful in vivo screens and mouse models. In Aim 1, I will elucidate the mechanism of the pro- metastatic action of RNF2 and assess its potential as a drug target. In Aim 2, I will determine the epigenomic landscape of non-metastatic cells and pro-metastatic cells in an effort to identify the cellular systems affected by pro-metastatic epigenetic changes. In Aim 3, I will take unbiased approach and use in vivo large scale screens in mice to identify epigenetic metastasis-promoters and suppressors. The mechanism for the `hits' from this screen will be studied as used for RNF2 in Aim 1 and 2. Overall, my training in epigenomic methods, mouse modeling and large scale in vivo screens will hone my scientific skills to prepare me for a successful independent career. In my independent phase, I will identify the mechanism of new metastasis-suppressors and promoters identified by proposed-screens. In addition, I will build mouse and zebrafish models to assess the ability of these genes as drug targets. In the end, by these studies I hope to identify new drug targets with epigenetic roles and possible epigenetic marks (on specific genomic loci) to use for devising new diagnostic methods.