Zhu Lihua, Zhao Ruibin, Huang Li, Mo Sisi, Yu Zhangbin, Jiang Li, Qiao Lixing
Institute of clinical, Jiangsu Health Vocational College, Nanjing, China.
Department of Pediatrics, Nanjing General Hospital, Nanjing, China.
Cell Physiol Biochem. 2018;49(6):2264-2276. doi: 10.1159/000493829. Epub 2018 Oct 2.
BACKGROUND/AIMS: Periventricular white matter damage (PWMD) is the predominant neurologic lesion in preterm infants who survive brain injury. In this study, we assessed the global changes in and characteristics of the transcriptome of circular RNAs (circRNAs) in the brain tissues of rats with PWMD.
We compared the expression profiles of circRNAs in brain samples from three rats with PWMD and three paired control tissues using deep RNA sequencing. Bioinformatics analysis was applied to investigate these differentially expressed circRNAs, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis was performed to confirm the results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict associated cell signaling pathways and functions. Network analysis was performed to predict circRNAs-microRNAs, and target genes related to PWMD.
A total of 2151 more reliable circRNAs were dysregulated in the brain tissues of rats with PWMD, indicating a potential role in the condition. Of the 98 circRNAs significantly differentially expressed in rat brains with PWMD (P< 0.05), 52 were significantly over-expressed and 46 were significantly under-expressed. The expression profiles of seven of 10 randomly selected circRNAs were confirmed by qRT-PCR analysis. The glutamatergic synapse pathway and the VEGF signaling pathway, both associated with hypoxia/ischemia induced brain damage, were inriched. Relationship between miRNA (rno-miR-433-3p and rno-miR-206-3p) and HIF-1α were evident and potential associations between chr6: 48820833|48857932 and their target genes (rno-miR-433-3p and rno-miR-206-3p) were identified.
The distinct expression patterns of circRNAs in the brain tissues of rats with PWMD suggest that circRNAs actively respond to hypoxia-ischemia. These findings could assist the development of novel diagnostic and therapeutic targets for PWMD therapy.
背景/目的：脑室周围白质损伤（PWMD）是脑损伤存活早产儿的主要神经病变。在本研究中，我们评估了PWMD大鼠脑组织中环状RNA（circRNA）转录组的整体变化及其特征。
我们使用深度RNA测序比较了三只PWMD大鼠和三个配对对照组织的脑样本中circRNA的表达谱。应用生物信息学分析来研究这些差异表达的circRNA，并进行定量逆转录聚合酶链反应（qRT-PCR）分析以证实结果。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析以预测相关的细胞信号通路和功能。进行网络分析以预测circRNA-微RNA以及与PWMD相关的靶基因。
PWMD大鼠脑组织中共有215个更可靠的circRNA表达失调，表明其在该病症中具有潜在作用。在PWMD大鼠脑中显著差异表达的98个circRNA中（P<0.05），52个显著过度表达，46个显著低表达。通过qRT-PCR分析证实了10个随机选择的circRNA中的7个的表达谱。与缺氧/缺血诱导的脑损伤相关的谷氨酸能突触途径和VEGF信号通路均得到富集。miRNA（rno-miR-433-3p和rno-miR-206-3p）与HIF-1α之间的关系明显，并且鉴定了chr6:48820833|48857932与其靶基因（rno-miR-433-3p和rno-miR-206-3p）之间的潜在关联。
PWMD大鼠脑组织中circRNA的独特表达模式表明circRNA对缺氧缺血有积极反应。这些发现有助于开发用于PWMD治疗的新型诊断和治疗靶点。
