Analysis of the Cancer Imprintome and its Associated Long Non-Coding RNAs

很明显，等位基因特异性甲基化--以及作为其重要结果之一的等位基因表达--比印迹作用广泛得多。然而，对这一现象的普遍性和重要性缺乏全球观点。在这里，我们建议从进化论的角度和为了更好地了解单等位基因效应在癌症中的影响，对这些现象进行系统的研究。拟议工作方案的一个重要方面是开发一个易于使用的工作流程工具包，用于检测单等位基因DNA甲基化和单等位基因转录，并整合这两种重要的数据类型。该项目旨在重新利用大规模协调工作中已经公开获得的广泛的亚硫酸氢盐和RNA-seq数据集，例如国际癌症测序联盟。为了涵盖进化层面，将考虑几个哺乳动物物种的现有数据，并将其与人类和老鼠的数据进行直接比较。然而，精心调控的DNA甲基化不仅限于哺乳动物，而且在群居昆虫中也发挥着关键作用。因此，我们还将考虑节肢动物物种中的等位特异性效应和种级差异，特别是在蜜蜂和蚂蚁中。性别特异的基因表达和DNA甲基化与多种疾病的诊断效率和临床结果的差异有关。因此，在拟议研究的背景下，我们将评估等位基因特异性效应的性别差异，包括DNA甲基化和转录输出。该项目的目的是在全基因组水平上对等位基因特异效应的分布、可变性和进化可塑性提供坚实的理解。

It has become clear that allel-specific methylation — and allel-specific gene expression as one of its important consequences — are much more wide-spread than imprinting. Nevertheless, a global view on the prevalence and importance of this phenomenon is lacking. Here, we propose to survey these phenomena systematically both from an evolutionary perspective and with the aim of obtaining a better understanding of the impact of monoallelic effects in cancer. An important aspect of the proposed work program is to develop a readily usable toolkit of workflows for the detection of monoallelic DNA methylation and monoallelic transcription, and for the integration of these two important data types. The project is designed to re-use the extensive bisulfite and RNA-seq data sets already publicly available from large-scale coordinated efforts such as the International Cancer Sequencing Consortium. In order to cover the evolutionary dimension, available data from several mammalian species will be considered in direct comparison to human and mouse data. Elaborate regulated DNA methylation is not limited to mammals, however, but also plays a key role in social insects. We will therefore also consider allel-specific effects and caste-differences in arthropod species, in particular in bees and ants. Sex-specific gene expression and DNA methylation has been implicated in differences in diagnostic efficiency and clinical outcomes in a wide array of disease entities. In the context of the proposed research we will therefore assess sex-specific differences of allel-specific effects, both with regards to DNA methylation and transcriptional output. The aim of the project is to provide a solid understanding of distribution, variability, and evolutionary plasticity of allel-specific effects at a genome-wide level.