脑白质高信号伴认知功能障碍患者环状RNA的差异性表达

Differential expression of circular RNA in patients with white matter hyperintensity and cognitive impairment

目的:脑白质高信号(white matter hyperintensity,WMH)是导致认知功能障碍的重要因素,机制目前仍未阐明。近年来研究发现环状RNA(circular RNA,circRNA)在脑血管疾病中存在差异性表达。本研究旨在分析circRNA在WMH伴认知功能障碍患者外周血单个核细胞中的表达谱,筛选其中差异性表达的circRNA,探讨circRNA在WMH伴认知功能障碍中的作用。方法:利用circRNA基因芯片检测WMH伴认知障碍者、WMH不伴认知障碍者及正常对照者(各纳入3例,男女比为2:1)外周血单个核细胞circRNA表达谱。筛选WMH伴认知障碍者的差异性表达circRNA,差异性表达circRNA的筛选标准为表达差异倍数变化(fold change,FC)≥2.0(|log_(2)FC≥1)且P<0.05。采用TargetScan和miRanda靶基因分析软件预测相关靶miRNA,Genespring软件预测靶基因。结果:与对照组比较,WMH伴认知障碍组显著上调的circRNA有5条,下调的有3条;WMH不伴认知障碍组显著上调的circRNA有8条,下调的有2条。WMH伴认知障碍组的circRNA表达谱分别与WMH不伴认知障碍组、对照组比较,未发现共同差异表达的circRNA;与对照组比较,WMH伴认知障碍组、WMH不伴认知障碍组的circRNA表达谱中hsa_circ_0092222均表达上调,hsa_circ_0000662和hsa_circ_0083773均表达下调,且它们在2组间的表达差异无统计学意义(均P>0.05)。预测到hsa_circ_0092222有2个靶miRNA(hsa-miR-19a-3p、hsa-miR-19b-3p),靶基因为核糖体蛋白S4,Y连锁1(ribosomal protein S4, Y-linked 1,RPS4Y1);hsa_circ_0000662有1个靶miRNA(hsa-miR-194),靶基因为轴抑制因子1(axis inhibitor 1, AXIN1);hsa_circ_0083773有7个靶miRNA,靶基因为重组清道夫受体A类成员3(recombinant scavenger receptor class A member 3,SCARA3)。结论:WMH患者的circRNA表达谱发生了显著变化;差异性表达的circRNA可能是导致脑白质出现高信号的原因;hsa_circ_0092222、hsa_circ_0000662、hsa_circ_0083773可能靶向吸附靶miRNA,调节靶基因的表达,通过Janus激酶2(Janus kinase 2,JAK2)/信号转导与转录活化因子3(signal transducers and activators of transcription,STAT3)信号通路、Wnt信号通路导致脑白质的损伤。未发现circRNA表达谱在WMH伴与不伴认知障碍患者中的显著差异,WMH患者出现认知障碍可能有其他发病机制。

Objective: White matter hyperintensity(WMH) is an important factor leading to cognitive impairment, and the mechanism has not been clarified. In recent years, studies have found that circular RNA(circRNA) has differential expression in cerebrovascular diseases. This study aims to analyze the expression profile of circRNA in peripheral blood mononuclear cell(PBMC) of patients with WMH with cognitive impairment, to screen the differentially expressed circRNA, and to explore the possible role of circRNA in WMH with cognitive impairment.Methods: Circ RNA microarray was used to detect the circRNA expression profile of PBMC in patients with WMH with cognitive impairment, and in patients with WMH without cognitive impairment as well as in normal controls(3 cases each, male to female ratio of 2 : 1). The differentially expressed circRNA in patients with WMH with cognitive impairment was screened. The screening criteria for differentially expressed circRNA was fold change(FC) ≥2.0(|log_(2)FC ≥1) and P<0.05. Target Scan and miRanda target gene analysis software were used to predict the relevant target miRNA, and Genespring software was used to predict the target genes.Results: Compared with the control group, there were 5 significantly up-regulated circRNA and 3 down-regulated circRNA in the WMH with cognitive impairment group;8 circRNA were significantly up-regulated and 2 were down-regulated in the WMH without cognitive impairment group. When compared with the WMH with cognitive impairment group, no co-differentially expressed circRNA was found in WMH without cognitive impairment group and control group. Compared with the control group, the expression of hsa_circ_0092222 was up-regulated and the expressions of hsa_circ_0000662 and hsa_circ_0083773 were down-regulated in the WMH with cognitive impairment group and the WMH without cognitive impairment group, and there was no significant difference between the 2 groups(all P>0.05). Two target miRNA(hsa-miR-19a-3p and hsa-miR-19b-3p) of hsa_circ_0092222 were predicted, and the target gene was ribosomal protein S4, Ylinked 1(RPS4Y1). Hsa_circ_0000662 predicted a target miRNA(hsa-miR-194) with axis inhibitor 1(AXIN1) as the target gene. Hsa_circ_0083773 predicted 7 target miRNA, and the target gene was recombinant scavenger receptor class A member 3(SCARA3).Conclusion: The circRNA expression profile of patients with WMH is changed significantly. The differentially expressed circRNA may be the cause of WMH;Hsa_circ_0092222, hsa_circ_0000662, and hsa_circ_0083773 may regulate the expression of target genes by targeting adsorption of the target miRNA, leading to brain white matter damage through Janus kinase 2(JAK2)/signal transducers and activators of transcription(STAT3)signal pathway and Wnt signal pathway. There is no significant difference in circRNA expression profile between WMH with or without cognitive impairment. Cognitive impairment in patients with WMH may have other reasons.