Epigenetic plasticity in tumor initiation and evolution

项目概要： 在不同的细胞类型中，基因组DNA被包装到染色质中的方式调节基因活性， 这一过程被称为“表观遗传学”。表观遗传控制在几乎所有形式的癌症中被破坏， 许多其他人类疾病。这可能通过染色质调节因子的突变、环境调节因子的突变和细胞内的细胞因子的突变而发生。 暴露于改变染色质结构或不适当的发育线索。有巨大 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机制的理解，如何表观遗传缺陷， 促进肿瘤，或如何在临床干预中调节它们。 拟议的项目将寻求一种新的，统一的模型，表观遗传病变如何驱动肿瘤 启动和进化。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， 其允许癌前或恶性细胞随机取样替代基因调节程序。 选择采用赋予适应性（增殖、耐受性等）的程序的细胞，并且它们的表观遗传 通过细胞分裂维持的状态，产生新的谱系，并最终导致恶性进展。 新建立的用于剖析、监测和调节表观遗传地貌的技术， 单细胞水平，提供了一个独特的机会，以测试这一假设和表征的基础 机制等我们将首先集中在典型的病变，驱动脑肿瘤的启动和演变。的 第一个例子是异柠檬酸脱氢酶（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。第二个例子是应激诱导的组蛋白去甲基化， 它允许癌症干细胞进入原始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， 进一步创新新技术。然后，我们将探讨可塑性在多大程度上属于其他 致癌性病变和具有表观遗传病因的其它疾病。 总之，本研究将深入研究表观遗传失调的机制， 肿瘤发生的可塑性这项研究有可能从根本上改变目前对表观遗传调控的看法 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.