A-to-I editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma
A-to-I editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma
复制标题
气道细胞中miR-200 b-3 p的A-to-I编辑与中度至重度哮喘相关
DOI：
10.1183/13993003.03862-2020
复制
发表时间：
2021-07-01
影响因子：
24.3
通讯作者：
Ober, Carole
中科院分区：
文献类型：
--
作者：
Magnaye, Kevin M.;Naughton, Katherine A.;Ober, Carole
背景：哮喘是一种以持续气道炎症为特征的慢性肺部疾病。支气管上皮细胞中microRNA介导的基因沉默的改变已被报道在哮喘，但ADAR介导的microRNA编辑在asthma remains unexplored.Methods：我们首先确定了A-to-I编辑位点的microRNA在支气管上皮细胞从142例成人哮喘病例和对照。A-to-I编辑的网站与哮喘严重程度和哮喘临床指标的相关性进行了测试。配对的RNA-seq数据用于进行途径富集并测试与未编辑和编辑的microRNA的生物信息学预测的靶基因的关联。在这些microRNA中检测到的19个A-to-I编辑位点中，与对照相比，病例中miR-200 b-3 p第5位的一个位点的编辑频率较低（P=0.013），尤其是与中度（P=0.029）和重度（P=3.9x10（-4））哮喘患者相比，但与轻度（P=0.38）哮喘患者相比。生物信息学预测揭示了经编辑的miR-200 b-3 p的232个靶基因，其富集了IL-4和干扰素γ信号传导途径，并且包括SOCS 1（细胞因子信号传导抑制因子1）基因。与对照组相比，SOCS 1在中度（P=0.017）和重度（P=5.4x10（-3））哮喘病例中的表达更高。结论：中重度哮喘患者下气道细胞中miR-200 b-3 p第5位A-to-I编辑减少，可能导致SOCS 1过表达和细胞因子信号通路受损。我们提出ADAR介导的编辑作为一种表观遗传机制，有助于成年期中度至重度哮喘的特征。
Background: Asthma is a chronic lung disease characterized by persistent airway inflammation. Altered microRNA-mediated gene silencing in bronchial epithelial cells has been reported in asthma, yet ADAR-mediated microRNA editing in asthma remains unexplored.Methods: We first identified A-to-I edited sites in microRNAs in bronchial epithelial cells from 142 adult asthma cases and controls. A-to-I edited sites were tested for associations with asthma severity and clinical measures of asthma. Paired RNA-seq data was used to perform pathway enrichments and test for associations with bioinformatically predicted target genes of the unedited and edited microRNAs.Results: Of 19 A-to-I edited sites detected in these microRNAs, one site at position 5 of miR-200b-3p was edited less frequently in cases compared to controls (P=0.013), and especially compared to cases with moderate (P=0.029) and severe (P=3.9x10(-4)), but not mild (P=0.38), asthma. Bioinformatic prediction revealed 232 target genes of the edited miR-200b-3p, which were enriched for both IL-4 and interferon gamma signaling pathways and included the SOCS1 (suppressor of cytokine signaling 1) gene. SOCS1 was more highly expressed in moderate (P=0.017) and severe (P=5.4x10(-3)) asthma cases compared to controls. Moreover, both miR-200b-3p editing and SOCS1 were associated with BAL eosinophil levels.Conclusion: Reduced A-to-I editing of the 5th position of miR-200b-3p in lower airway cells from moderate-to-severe asthmatics may lead to overexpression of SOCS1 and impaired cytokine signaling. We proposed ADAR-mediated editing as an epigenetic mechanism contributing to features of moderate-to-severe asthma in adulthood.