Shared Instrumentation Grant

描述（由申请人提供）：癌症研究依赖于能够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，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，因为细胞向恶性发展，并获得各种属性，如耐药性。冷泉港实验室的癌症研究一直处于这种“癌症基因组学”方法以及导致这些疾病和其他疾病的表观遗传机制研究的前沿。在应用中总结了研究课题的例子，从甲基化在乳腺癌和化疗耐药AML中的作用到复制诱导衰老。此外，我们计划研究模式动物和植物的表观基因组图谱，这些动物和植物的表观遗传图谱经历了发育程序化的变化，并使用RNA干扰来指导DNA甲基化和组蛋白修饰模式。为了做到这一点，我们正在申请资金从罗氏应用科学公司购买基因组测序仪FLX，它可以可靠地确定表观基因组的序列，即使胞嘧啶转化为尿嘧啶，因为较长的读取长度允许明确地映射回参考基因组。公共卫生相关性：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，很明显，除了我们的基本DNA结构之外，对其进行修改，例如在特定位置添加甲基，也至关重要。甲基化DNA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，还可能导致癌症和其他疾病。我们需要的设备将使我们能够非常详细和大规模地检查基因组中甲基化的变化，以便我们能够更好地了解这一过程在正常生物过程中是如何发生的，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.