Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, California, United States of America.
Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2022 Aug 25;17(8):e0273524. doi: 10.1371/journal.pone.0273524. eCollection 2022.
Hypoxia plays a major role in the etiology and pathogenesis of most of the leading causes of morbidity and mortality, whether cardiovascular diseases, cancer, respiratory diseases or stroke. Despite active research on hypoxia-signaling pathways, the understanding of regulatory mechanisms, especially in specific tissues, still remain elusive. With the accessibility of thousands of potentially diverse genomic datasets, computational methods are utilized to generate new hypotheses. Here we utilized Boolean implication relationship, a powerful method to probe symmetrically and asymmetrically related genes, to identify novel hypoxia related genes. We used a well-known hypoxia-responsive gene, VEGFA, with very large human expression datasets (n = 25,955) to identify novel hypoxia-responsive candidate gene/s. Further, we utilized in-vitro analysis using human endothelial cells exposed to 1% O2 environment for 2, 8, 24 and 48 hours to validate top candidate genes. Out of the top candidate genes (n = 19), 84% genes were previously reported as hypoxia related, validating our results. However, we identified FAM114A1 as a novel candidate gene significantly upregulated in the endothelial cells at 8, 24 and 48 hours of 1% O2 environment. Additional evidence, particularly the localization of intronic miRNA and numerous HREs further support and strengthen our finding. Current results on FAM114A1 provide an example demonstrating the utility of powerful computational methods, like Boolean implications, in playing a major role in hypothesis building and discovery.
缺氧在大多数主要发病率和死亡率的病因和发病机制中起着主要作用，无论是心血管疾病、癌症、呼吸疾病还是中风。尽管对缺氧信号通路进行了积极的研究，但对调节机制的理解，特别是在特定组织中，仍然难以捉摸。随着数以千计的潜在多样化基因组数据集的可及性，计算方法被用于生成新的假设。在这里，我们利用布尔蕴涵关系，一种用于探测对称和非对称相关基因的强大方法，来识别新的与缺氧相关的基因。我们使用了一个众所周知的缺氧反应基因 VEGFA，以及非常大的人类表达数据集（n = 25955）来识别新的缺氧反应候选基因。此外，我们利用人类内皮细胞在 1%O2 环境中暴露 2、8、24 和 48 小时的体外分析来验证顶级候选基因。在顶级候选基因（n = 19）中，84%的基因之前被报道为与缺氧相关，验证了我们的结果。然而，我们鉴定出 FAM114A1 是内皮细胞在 1%O2 环境中 8、24 和 48 小时显著上调的新候选基因。额外的证据，特别是内含子 miRNA 和许多 HREs 的定位，进一步支持和加强了我们的发现。目前关于 FAM114A1 的结果提供了一个例子，证明了强大的计算方法，如布尔蕴涵，在假设构建和发现中起着重要作用。
