Integrative approach to studying LncRNA functions

对母体R01GM123037 "研究LncRNA功能的综合方法"的补充 近年来的研究表明lncRNA与阿尔茨海默病等多种神经系统疾病有关 疾病（AD）。首先，lncRNA影响AD的发病机制，因为它们的不同功能作用，从 表观遗传调节例如，β位点淀粉样前体蛋白裂解酶-1反义转录物 （BACE1-AS）是从β位点APP裂解酶-1（BACE1）的相对链转录的lncRNA 基因座细胞应激增加了BACE1-AS水平，这反过来刺激了BACE1表达， 增强APP加工和Ab1 - 42生产。Ab1 - 42水平升高可进一步促进BACE1-AS 过度表达和APP加工级联以前馈方式。第二，积累证据 表明microRNA在AD的发病机制中起关键作用。因为90%的SNP 与疾病相关的基因位于非编码区，lncRNA起着miRNA海绵的作用， RNA水平的编辑，其具有与lncRNA中的单核苷酸变体类似的效果，可以导致异常的转录。 AD基因表达调控第三，lncRNA中的另一种致病性转录后修饰是 选择性剪接（AS）。G蛋白偶联受体51（GPR51）基因内含子3中的17A基因， 如.与对照组相比，AD中17 A lncRNA上调，17 A中AS事件损害GABA B 信号传导，增强A β分泌。已知的lncRNA的作用和功能已经积累。 然而，对于转录后修饰的lncRNA， 编辑或选择性剪接事件。因此，迫切需要开发新的工具， 分析转录后修饰的lncRNA在AD中的系统性潜在功能影响， 基因组并预测其调控机制。在这里，我们建议开发一个集成系统， 转录后修饰事件的基于转录组测序数据的功能注释 AD中的lncRNA基于来自ADSP联盟的AD测序数据和其他NIH控制的AD数据 集.我们的多学科团队提出了以下目标：（1）我们将开发功能机制 通过研究miRNA结合位点的获得/丧失来预测lncRNA的RNA编辑事件， 它靶向AD基因（我们整合了约1,500个AD基因），由于RNA编辑， RNA编辑+/-基团之间的表达影响和研究lncRNA的相对能量变化 二级结构。(2)我们将开发lncRNA的AS事件的功能机制预测， 在lncRNA中识别AD特异性/相关AS事件，将lncRNA表达与AD基因的AS相关， 异构体，研究由于AS事件和SNP/SV诱导的AS事件导致的miRNA结合位点的获得/丧失。 我们的研究将集中在AD相关的lncRNA，以确定这些对AD基因和AD的表观遗传影响 致病机制本补充文件在我们提出的母文件R01GM123037的范围内 开发生物信息学工具来研究lncRNA在癌症中的功能。

Supplementary to the parent R01GM123037 “Integrative approach to studying LncRNA functions” The recent studies showed that lncRNAs were involved in many neurological diseases such as Alzheimer's disease (AD). First, lncRNAs impact AD pathogenesis because of their diverse functional effects from the epigenetic regulation. For example, β-site amyloid precursor protein cleaving enzyme-1 antisense transcript (BACE1-AS) is the lncRNA transcribed from the opposite strand of β -site APP cleaving enzyme-1 (BACE1) locus. Cell stress increased BACE1-AS levels, which in turn stimulates BACE1 expression, which could enhance APP processing and Ab1-42 production. Elevated Ab1-42 levels can further promote BACE1-AS overexpression and the APP processing cascade in a feedforward manner. Second, accumulating evidence shows that microRNAs play a critical role in the pathogenesis of AD. From the fact that ~ 90% of the SNPs associated with diseases are located in non-coding regions and lncRNA plays a role as a sponge of miRNAs, RNA-level editing, which has the similar effect as the single nucleotide variant in lncRNA, can result in aberrant gene expression regulation in AD. Third, another pathogenic post-transcriptional modification in lncRNA is the alternative splicing (AS). 17A mapped in intron 3 of G-protein-coupled receptor 51 gene (GPR51) undergoes AS. 17A lncRNA is upregulated in AD compared with control and AS event in 17A impairs the GABA B signaling, enhance Aβ secretion. The role and functions of the known lncRNAs have been accumulated. However, there is no deep functional annotation of post-transcriptionally modified lncRNAs that have RNA- editing or alternative splicing events in the AD. Therefore, there is an urgent need to develop new tools for analyzing the potential functional impact of the post-transcriptionally modified lncRNA systemically in the AD genome and predict their regulatory mechanisms. Here, we propose to develop an integrated system for transcriptomic sequencing data-based functional annotation of post-transcriptional modification events of lncRNAs in AD based on the AD sequencing data from ADSP consortium and other NIH controlled AD data sets. Our multidisciplinary team proposed the following aims: (1) We will develop functional mechanism prediction of lncRNAs' RNA-editing events through investigating the gain/loss of the binding sites of miRNAs, which targeting AD genes (we integrated ~ 1,500 AD genes.), due to RNA-editing with checking the expressional impact between RNA-editing +/- groups and studying the changed relative energy of lncRNA secondary structures. (2) We will develop functional mechanism prediction of lncRNAs' AS events through identifying AD-specific/associated AS events in lncRNAs, correlated lncRNA expressions with AD genes' AS isoforms, investigating the gain/loss of miRNA binding sites due to AS event, and SNP/SV-induced AS events. Our study will be focused on AD-related lncRNAs to identify epigenetic impact of these on AD genes and AD pathogenic mechanisms. This supplementary is within the scope of parent R01GM123037 where we proposed to develop Bioinformatics tools to study lncRNA functions for cancer.