Constructing A Transcriptomic Atlas of Retrotransposon in Alzheimer's Disease

AD患者的数量每年都在逐渐增加， 据估计，到2021年，AD患者的医疗保健费用为3350亿美元，预计到2050年将增加两倍。为了公共 健康和经济，了解AD遗传学并找到有效的AD预防和治疗方法， 重要.大量研究表明，AD是一种复杂的遗传性疾病，通常涉及基因组 结构调整和监管。因此，不仅需要研究常规基因、蛋白质， 以及它们的调节，还有AD中的其他遗传成分。逆转录转座子（RTEs）是DNA 复制自己并将其拷贝插入基因组的序列。有一些人对 研究反转录转座子的研究例如，已知由Tau介导的染色质松弛可导致细胞凋亡。 蛋白质积累可能过度激活反转录转座子。这种大规模的激活可能会引发一种先天的 免疫反应和破坏基因组，这可能导致神经变性。此外，一项研究表明， 抗病毒药物可以通过抑制其逆转录酶来抑制AD中RTEs的激活， 抑制导致神经变性的预防。这些研究表明， 反转录转座子在AD中的功能和作用将提供一个额外的和重要的方式来理解 RTEs在AD发病机制中的调节作用。然而，AD中RTEs的分子特征，如细胞 类型/性别特异性，仍然未知。表征RTE需要生成大规模RTE表达式 数据集。这些数据尚未公开，尽管AD研究界已经做出了巨大的努力， 努力生成大规模的死后AD转录组数据，包括约2，000名受试者的批量RNA-seq 和约260，000个细胞的单细胞核RNA-seq。因此，我们提出了两个具体目标，以执行第一个 通过建立AD研究RTE图谱资源系统研究RTE：目的1.来产生大规模的 通过对公开的AD转录组数据集进行挖掘和处理，得到RTE表达数据集。我们将扩大我们的 SalmonTE算法从AD转录组数据集在组织水平和单个水平上挖掘RTE表达 细胞分辨率目标2.通过使用以下工具表征RTE和AD患者，生成AD RTE图谱资源 统计和机器学习方法。我们将扩大我们的内部计算方法， 上下文特异性（例如，脑区、细胞类型和性别）。我们还将开发 使用RTE表达和多组学数据的无监督图神经网络来表征AD患者。 最后，我们将创建一个地图集网站，与AD研究社区分享我们的发现。成功 该项目的完成将提供1）新的计算方法来严格表征AD中的RTE，2） AD中背景特异性RTE的鉴定和使用RTE表达的AD患者的表征，和3） 一个注释良好的AD RTE图谱，以加深我们对AD分子基础的了解。

Project Summary The number of AD patients is gradually increasing every year, and the economic burden of health care of AD patients, estimated at $335 billion in 2021, is predicted to triple by 2050. In the interest of public health and the economy, understanding AD genetics and finding effective AD prevention and treatment are important. Numerous studies have suggested that AD is a complicated genetic disorder, often involving genomic structural changes and regulation. Thus, there is a strong need to investigate not only regular genes, proteins, and their regulations but also the other genetic components in AD. Retrotransposons (RTEs) are DNA sequences that copy themselves and insert their copies into the genome. There has been some interest in studying retrotransposons in AD research. For example, it is known that chromatin relaxation mediated by Tau protein accumulation may overly activate the retrotransposons. This massive activation may provoke an innate immune response and damage the genome, which can result in neurodegeneration. Moreover, a study showed that antiviral drugs could suppress activation of RTEs in AD by inhibiting their reverse transcriptase, and the suppression results in the prevention of neurodegeneration. These studies suggested that investigating the features and roles of retrotransposons in AD will provide an additional and important way to understand the regulations of RTEs in AD pathogenesis. However, molecular characteristics of the RTEs in AD, such as cell type-/sex-specificity, are still unknown. Characterizing RTEs requires generating large-scale RTE expression datasets. Such data has not been available publicly, although the AD research community has made tremendous efforts to generate large-scale postmortem AD transcriptome data, including bulk RNA-seq of ~2,000 subjects and single-cell nuclei RNA-seq of ~260,000 cells. Therefore, we propose two specific aims to perform the first systematic study of RTE by constructing an RTE atlas resource for AD study: Aim 1. To generate large-scale RTE expression datasets by mining and processing public AD transcriptome datasets. We will extend our SalmonTE algorithm to mine RTE expressions from AD transcriptome datasets at both tissue-level and single- cell resolution. Aim 2. To generate AD RTE atlas resources by characterizing RTEs and AD patients using statistical and machine learning methods. We will expand our in-house computational methods to calculate context-specificity (e.g., brain region, cell type, and sex) of each RTE in human AD brains. We will also develop an unsupervised graph neural network using RTE expression and multi-omics data to characterize AD patients. In the end, we will create an atlas website to share our findings with the AD research community. Successful completion of this project will provide 1) novel computational methods to rigorously characterize RTEs in AD, 2) identification of context-specific RTEs in AD and characterization of AD patients using RTE expression, and 3) a well-annotated AD RTE atlas to deepen our knowledge in the molecular basis of AD.