U. S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology, Division of Applied Regulatory Science, HFD-910, White Oak Federal Research Center, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA.
BMC Genomics. 2018 Apr 27;19(1):297. doi: 10.1186/s12864-018-4657-2.
Co-sequencing of messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA) across a time series (1, 3, 6, 24, and 48 h post injury) was used to identify potential miRNA-gene interactions during pancreatic injury, associate serum and tissue levels of candidate miRNA biomarkers of pancreatic injury, and functionally link these candidate miRNA biomarkers to observed histopathology. RNAs were derived from pancreatic tissues obtained in experiments characterizing the serum levels of candidate miRNA biomarkers in response to acute pancreatic injury in rats.
No correlation was discovered between tissue and serum levels of the miRNAs. A combination of differential gene expression, novel delayed anti-correlation analysis and experimental database interrogation was used to identify messenger RNAs and miRNAs that experienced significant expression change across the time series, that were negatively correlated, that were complementary in sequence, and that had experimentally supported relationships. This approach yielded a complex signaling network for future investigation and a link for the specific candidate miRNA biomarkers, miR-216a-5p and miR-217-5p, to cellular processes that were in fact the prominent histopathology observations in the same experimental samples. RNA quality bias by treatment was observed in the study samples and a statistical correction was applied. The relevance and impact of that correction on significant results is discussed.
The described approach allowed extraction of miRNA function from genomic data and defined a mechanistic anchor for these miRNAs as biomarkers. Functional and mechanistic conclusions are supported by histopathology findings.
通过对信使核糖核酸（mRNA）和微核糖核酸（miRNA）的时间序列（损伤后 1、3、6、24 和 48 小时）进行共测序，鉴定了胰腺损伤过程中潜在的 miRNA-基因相互作用，关联候选 miRNA 生物标志物的血清和组织水平，并将这些候选 miRNA 生物标志物与观察到的组织病理学联系起来。从实验中获得的胰腺组织中提取了 RNA，这些实验描述了候选 miRNA 生物标志物对大鼠急性胰腺损伤的血清水平的反应。
未发现 miRNA 的组织和血清水平之间存在相关性。采用差异基因表达、新的延迟反相关分析和实验数据库查询相结合的方法，鉴定了在整个时间序列中经历显著表达变化、负相关、互补序列且具有实验支持关系的信使 RNA 和 miRNA。这种方法产生了一个复杂的信号网络，用于进一步研究，并将特定的候选 miRNA 生物标志物 miR-216a-5p 和 miR-217-5p 与细胞过程联系起来，这些细胞过程实际上是同一实验样本中突出的组织病理学观察结果。研究样本中观察到了治疗引起的 RNA 质量偏差，并应用了统计校正。讨论了该校正对显著结果的相关性和影响。
所描述的方法允许从基因组数据中提取 miRNA 功能，并将这些 miRNA 定义为生物标志物的机制锚点。功能和机制结论得到组织病理学发现的支持。
