Epigenetic plasticity in tumor initiation and evolution

项目总结： 基因组DNA被包装成染色质-a的方式在不同类型的细胞中调节基因活性 这个过程被称为“表观遗传学”。表观遗传控制在几乎所有形式的癌症中都被破坏，在 许多其他人类疾病。这可能是通过环境中染色质调节因子的突变而发生的 暴露改变染色质结构，或不适当的发育线索。有巨大的 对“表观遗传疗法”在临床环境中纠正表观遗传缺陷的潜力的热情。 然而，我们目前缺乏连贯的模型或对表观遗传缺陷如何产生机制的理解。 促进肿瘤，或它们在临床干预中可能受到的调节。 拟议的项目将寻求一种新的、统一的模型来研究表观遗传病变如何驱动肿瘤。 启蒙和进化。我们假设大多数表观遗传损伤的一个关键功能是诱导可塑性， 它允许癌前或恶性细胞随机采样交替的基因调控程序。 选择采用赋予适合性(增殖、耐受性等)程序的细胞，并将其表观遗传学 通过细胞分裂来维持状态，产生新的血统，并最终导致恶性进展。 新建立的描述、监测和调节表观遗传景观的技术，包括在 单细胞水平，提供了一个独特的机会来检验这一假设并表征潜在的 机械装置。我们首先将重点放在驱动脑肿瘤启动和演变的样本病变上。这个 第一个样本是异柠檬酸脱氢酶(IDH)基因突变和相关的DNA超甲基化， 我们假设这会导致染色质边界和绝缘体的随机破坏，从而允许 癌基因的异常诱导。第二个样本是应激诱导的组蛋白去甲基化，我们 POST允许癌症干细胞获得原始的发育程序，并进化出药物耐受性。我们 将通过利用临床标本和实验模型来深入描述这些样本，并通过 进一步创新新技术。然后我们将探讨可塑性在多大程度上与 致癌性损害和其他具有表观遗传病因的疾病。 综上所述，这项拟议的研究将深入研究表观遗传去调控和 肿瘤发生中的可塑性。这项研究有可能从根本上改变目前关于表观遗传调控的观点 在人类疾病中，因此具有重要的生物医学意义。

Project Summary: Gene activity is modulated in different cell types by the way genomic DNA is packaged into chromatin – a process termed ‘epigenetics’. Epigenetic controls are disrupted in nearly all forms of cancer, as well as in many other human diseases. This may occur through mutation of chromatin regulators, environmental exposures that alter chromatin structure, or inappropriate developmental cues. There is enormous enthusiasm for the potential of ‘epigenetic therapies’ to correct epigenetic defects in clinical settings. However, we currently lack coherent models or mechanistic understanding of how epigenetic defects promote tumors, or how they might be modulated in clinical intervention. The proposed project will pursue a novel, unifying model for how epigenetic lesions drive tumor initiation and evolution. We hypothesize that a key function of most epigenetic lesions is to induce plasticity, which allows pre-malignant or malignant cells to stochastically sample alternate gene regulatory programs. Cells that adopt programs that confer fitness (proliferation, tolerance, etc) are selected, and their epigenetic state maintained through cell division, giving rise to a new lineage and, ultimately, to malignant progression. Newly established technologies for profiling, monitoring and modulating epigenetic landscapes, including at single cell level, provide a unique opportunity to test this hypothesis and characterize the underlying mechanisms. We will focus initially on exemplar lesions that drive brain tumor initiation and evolution. The first exemplar is isocitrate dehydrogenase (IDH) gene mutations and associated DNA hyper-methylation, which we hypothesize cause stochastic disruption of chromatin boundaries and insulators, thereby allowing aberrant induction of oncogenes. The second exemplar is stress-induced histone demethylation, which we posit allows cancer stem cells to access primitive developmental programs and evolve drug tolerance. We will deeply characterize these exemplars by leveraging clinical specimens and experimental models, and by further innovating new technologies. We will then explore the extent to which plasticity pertains to other oncogenic lesions and to other diseases with epigenetic etiologies. In summary, the proposed study will deeply investigate mechanisms of epigenetic deregulation and plasticity in tumorigenesis. The research has potential to radically alter current views of epigenetic regulation in human disease, and thus has important biomedical implications.