Shared Instrumentation Grant

描述(申请人提供)：癌症研究依赖于可以询问整个基因组的技术，检测导致疾病的缺失、拷贝数变异和点突变。越来越清楚的是，随着细胞向恶性发展，并获得各种属性，如耐药性，DNA和组蛋白修饰中的表观遗传损伤至少与遗传损伤一样重要，甚至可能更重要。冷泉港实验室的癌症研究一直处于这种“癌症基因组学”方法的前沿，以及对导致这些和其他疾病的表观遗传机制的研究。在应用中总结了研究主题的例子，从甲基化在乳腺癌和化疗耐药AML中的作用到复制诱导的衰老。此外，我们计划检查模型动物和植物的表观基因组图谱，这些动物和植物在表观遗传学图谱中经历发育程序性变化，并使用RNA干扰来指导DNA甲基化和组蛋白修饰模式。为此，我们正在申请资金从罗氏应用科学公司购买基因组Sequencer Flx仪器，该仪器可以可靠地确定表观基因组的序列，即使在胞嘧啶转化为尿嘧啶的情况下也是如此，因为更长的读取长度允许明确地映射回参考基因组。与公共健康相关：随着我们更多地了解信息是如何存储在我们的基因组中并控制生物过程的，显然除了我们的基本DNA结构外，对其进行修改，如在特定位置添加甲基是至关重要的。DNA甲基化区域的变化可以改变正常发育过程中的基因表达，如果控制不当，还会导致癌症，甚至可能导致其他疾病。我们要求的设备将使我们能够非常详细和非常大规模地检查基因组甲基化的变化，以便我们能够更好地了解这一过程是如何在正常的生物过程中发生的，以及它在癌症中调节哪些基因。

DESCRIPTION (provided by applicant): Cancer research relies on technologies that can interrogate the entire genome, detecting deletions, copy number variants and point mutations responsible for disease. It is becoming increasingly clear that epigenetic lesions in DNA and histone modification are at least as important, and probably more important, than genetic lesions as cells progress towards malignancy, and acquire various attributes, such as drug-resistance. Cancer research at Cold Spring Harbor Laboratory has been at the forefront of this "cancer genomics" approach, as well as research in epigenetic mechanisms that contribute to these and other diseases. Examples of research topics are summarized in the application, ranging from the role of methylation in breast cancer and chemoresistant AML to replication-induced senescence. Further, we plan to examine epigenomic profiles in model animals and plants, which undergo developmentally programmed changes in epigenetic profiles, and which use RNA interference to guide DNA methylation and histone modification patterns. To do this, we are requesting funds to purchase a Genome Sequencer FLX instrument from Roche Applied Science, which can reliably determine the sequence of the epigenome, even when cytosines are converted to uracil, because longer read lengths permit unambiguous mapping back to the reference genome. PUBLIC HEALTH RELEVANCE: As we learn more about how information is stored in our genome and controls biological processes it has become apparent that in addition to our basic DNA structure, modifications to it, such as the addition of methyl groups in specific places is of crucial importance. Changes in methylated DNA regions can change gene expression in normal development as well as lead to cancer if and possibly other diseases if not properly controlled. We are requesting equipment that will allow us to examine, in great detail and at very large scale, the changes to methylation in the genome so that we can better understand how this process occurs in normal biological processes as well as which genes it regulates in cancer.