Genome-Wide Posttranscriptional Dysregulation by MicroRNAs in Human Asthma as Revealed by Frac-seq.
Genome-Wide Posttranscriptional Dysregulation by MicroRNAs in Human Asthma as Revealed by Frac-seq.
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DOI：
10.4049/jimmunol.1701798
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发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Sanchez-Elsner T
中科院分区：
文献类型：
--
作者：
Martinez-Nunez RT;Rupani H;Platé M;Niranjan M;Chambers RC;Howarth PH;Sanchez-Elsner T
MicroRNAs是一种小的非编码rna，它在转录后抑制基因表达，几乎涉及所有的生物过程。虽然单个microrna的作用通常被研究，但对多个microrna在全基因组中的作用研究较少。我们利用fracseq技术，在健康对照和严重哮喘患者的人原代支气管上皮中评估了microrna的全基因组表达、总（细胞质）和翻译（多核糖体结合）mRNA水平。严重哮喘是一种慢性气道炎症性疾病，其特点是对治疗反应差。我们发现基因（=一个基因的所有亚型）和mRNA亚型在哮喘中差异表达，仅通过多核糖体结合的mRNA（例如IL1A和LTB基因或ITGA6和ITGA2选择性剪接的亚型）揭示了与支气管上皮相关的新的炎症和结构病理生理机制。基因表达（=一个基因的所有同工异构体）和mRNA表达分析揭示了不同的候选分子和生物学途径，差异表达的多核糖体结合mRNA和总mRNA也几乎没有重叠。我们揭示了六种失调的microRNA中心，占所有microRNA靶向的90%，表现出对多核糖体结合的mrna的偏好。在健康供体的支气管上皮细胞中转染该中心可模拟哮喘特征。我们的工作证明了人类哮喘中广泛的转录后基因失调，其中microrna发挥核心作用，说明了在研究人类疾病时评估转录后基因表达的可行性和重要性。
MicroRNAs are small non-coding RNAs that inhibit gene expression post-transcriptionally, implicated in virtually all biological processes. Although the effect of individual microRNAs is generally studied, the genome-wide role of multiple microRNAs is less investigated. We assessed paired genome-wide expression of microRNAs with total (cytoplasmic) and translational (polyribosome-bound) mRNA levels employing Frac-seq in human primary bronchoepithelium from healthy controls and severe asthmatics. Severe asthma is a chronic inflammatory disease of the airways characterized by poor response to therapy. We found genes (=all isoforms of a gene) and mRNA isoforms differentially expressed in asthma, with novel inflammatory and structural pathophysiological mechanisms related to bronchoepithelium disclosed solely by polyribosome-bound mRNAs (e.g., IL1A and LTB genes or ITGA6 and ITGA2 alternatively spliced isoforms). Gene expression (=all isoforms of a gene) and mRNA expression analysis revealed different molecular candidates and biological pathways, with differentially expressed polyribosome-bound and total mRNAs also showing little overlap. We reveal a hub of six dysregulated microRNAs accounting for ~90% of all microRNA targeting, displaying preference for polyribosome-bound mRNAs. Transfection of this hub in bronchial epithelial cells from healthy donors mimicked asthma characteristics. Our work demonstrates extensive post-transcriptional gene dysregulation in human asthma, where microRNAs play a central role, illustrating the feasibility and importance of assessing post-transcriptional gene expression when investigating human disease.
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影响因子：
4.6
作者：
Dassi E;Greco V;Sidarovich V;Zuccotti P;Arseni N;Scaruffi P;Tonini GP;Quattrone A
通讯作者：
Quattrone A
影响因子：
24.3
作者：
Chung, Kian Fan;Wenzel, Sally E.;Teague, W. Gerald
通讯作者：
Teague, W. Gerald
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1126/science.1215691
发表时间：
2012-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Djuranovic S;Nahvi A;Green R
通讯作者：
Green R
影响因子：
14.2
作者：
Al-Muhsen, Saleh;Johnson, Jill R.;Hamid, Qutayba
通讯作者：
Hamid, Qutayba