Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease.
Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease.
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DOI：
10.1186/1752-0509-5-56
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发表时间：
2011-04-25
影响因子：
--
通讯作者：
Kreidberg JA
中科院分区：
文献类型：
--
作者：
Pandey P;Qin S;Ho J;Zhou J;Kreidberg JA
常染色体显性多囊肾病 (ADPKD) 的特点是整个肾实质内形成囊肿。它是由 PKD1 和 PKD2 两个基因之一的突变引起的。缺乏功能性 Pkd1 (Pkd1-/-) 的小鼠在胚胎发生过程中会出现快速进展的囊性疾病，并可作为研究人类 ADPKD 的模型。全基因组转录组重编程以及影响 Pkd1-/- 中囊肿形成的起始和进展的 micro-RNA (miRNA) 的可能作用还有待研究。 miRNA 是小的、调节性非编码 RNA，参与广泛的生物过程。它们的表达水平在肾癌、糖尿病肾病和多囊肾等多种疾病中发生改变。我们通过在第 14.5 天和 17.5 天的胚胎肾脏中进行全局基因表达谱分析，检查了 Pkd1-/- 模型中调节肾囊肿形成和生长的分子途径。基因本体论和基因集富集分析用于识别 Pkd1-/- 肾脏中代表性过高的信号通路。我们发现 Pkd1-/- 肾脏中发育、代谢和信号通路（例如 Wnt、钙、TGF-β 和 MAPK）失调。使用比较转录组学方法，我们确定了与人类 ADPKD 的相似性和差异：观察到错误调节途径之间的途径水平有约 50% 的重叠。然后，通过使用计算方法（TargetScan、miRanda、microT 和 miRDB），我们预测了针对差异表达 mRNA 的 miRNA。通过 qPCR 证实了 9 个候选 miRNA、miR-10a、-30a-5p、-96、-126-5p、-182、-200a、-204、-429 和 -488 以及 16 个基因的差异表达。此外，还预测了 14 种候选 miRNA:mRNA 相互作用。一些高度调控的基因和通路被预测为 miRNA 的靶标。我们在 Pkd1-/- 模型中描述了 PKD 进展过程中的全局转录重编程。我们提出了一个涉及囊肿形成和生长的信号事件级联模型。我们的结果表明，一些 miRNA 可能参与调节 ADPKD 的信号通路。我们进一步描述了 ADPKD 中新的假定 miRNA:mRNA 特征，这将为了解这种人类常见遗传病的发病机制提供更多见解。
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation throughout the kidney parenchyma. It is caused by mutations in either of two genes, PKD1 and PKD2. Mice that lack functional Pkd1 (Pkd1-/-), develop rapidly progressive cystic disease during embryogenesis, and serve as a model to study human ADPKD. Genome wide transcriptome reprogramming and the possible roles of micro-RNAs (miRNAs) that affect the initiation and progression of cyst formation in the Pkd1-/- have yet to be studied. miRNAs are small, regulatory non-coding RNAs, implicated in a wide spectrum of biological processes. Their expression levels are altered in several diseases including kidney cancer, diabetic nephropathy and PKD. We examined the molecular pathways that modulate renal cyst formation and growth in the Pkd1-/- model by performing global gene-expression profiling in embryonic kidneys at days 14.5 and 17.5. Gene Ontology and gene set enrichment analysis were used to identify overrepresented signaling pathways in Pkd1-/- kidneys. We found dysregulation of developmental, metabolic, and signaling pathways (e.g. Wnt, calcium, TGF-β and MAPK) in Pkd1-/- kidneys. Using a comparative transcriptomics approach, we determined similarities and differences with human ADPKD: ~50% overlap at the pathway level among the mis-regulated pathways was observed. By using computational approaches (TargetScan, miRanda, microT and miRDB), we then predicted miRNAs that were suggested to target the differentially expressed mRNAs. Differential expressions of 9 candidate miRNAs, miRs-10a, -30a-5p, -96, -126-5p, -182, -200a, -204, -429 and -488, and 16 genes were confirmed by qPCR. In addition, 14 candidate miRNA:mRNA reciprocal interactions were predicted. Several of the highly regulated genes and pathways were predicted as targets of miRNAs. We have described global transcriptional reprogramming during the progression of PKD in the Pkd1-/- model. We propose a model for the cascade of signaling events involved in cyst formation and growth. Our results suggest that several miRNAs may be involved in regulating signaling pathways in ADPKD. We further describe novel putative miRNA:mRNA signatures in ADPKD, which will provide additional insights into the pathogenesis of this common genetic disease in humans.
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Harris PC;Torres VE
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