miR-638 regulates gene expression networks associated with emphysematous lung destruction.
miR-638 regulates gene expression networks associated with emphysematous lung destruction.
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作者：
Christenson SA;Brandsma CA;Campbell JD;Knight DA;Pechkovsky DV;Hogg JC;Timens W;Postma DS;Lenburg M;Spira A
慢性阻塞性肺疾病（COPD）是一种异质性疾病，其特征是不同程度的肺气肿性肺破坏和小气道疾病，每种疾病对临床结果的影响不同。关于microrna如何特异性地促进肺气肿表型，我们知之甚少。我们研究了全基因组microRNA表达如何随着区域性肺气肿严重程度而改变，以及这些microRNA如何调节疾病相关基因表达网络。我们分析了6名COPD吸烟者和2名对照者（8个区域× 8个肺= 64个样本）不同肺气肿程度肺不同区域的microrna。用平均线性截距量化区域肺气肿严重程度。在同一样品中整合全基因组microRNA和基因表达数据，构建共表达网络。为了验证这些网络，在人肺成纤维细胞中干扰候选microrna。63个microrna的表达水平在区域性肺气肿中发生改变（P < 0.05）。一个子集，包括miR-638、miR-30c和miR-181d，其表达水平与其预测的mRNA靶标相关。与这些microrna相关的基因在与肺气肿病理生理相关的途径中富集（例如，氧化应激和加速衰老）。抑制肺成纤维细胞中miR-638的表达导致这些相同的肺气肿相关通路的调节。miR-638在这些通路中的基因靶点与miR-638在肺气肿中的表达呈负相关。我们的研究结果表明，microrna随着区域性肺气肿严重程度的改变而改变，并调节疾病相关的基因表达网络。此外，miR-638可能调控肺气肿肺组织和肺成纤维细胞中氧化应激反应和衰老相关的基因表达途径。
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how genome-wide microRNA expression is altered with regional emphysema severity and how these microRNAs regulate disease-associated gene expression networks. We profiled microRNAs in different regions of the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified by mean linear intercept. Whole genome microRNA and gene expression data were integrated in the same samples to build co-expression networks. Candidate microRNAs were perturbed in human lung fibroblasts in order to validate these networks. The expression levels of 63 microRNAs (P < 0.05) were altered with regional emphysema. A subset, including miR-638, miR-30c, and miR-181d, had expression levels that were associated with those of their predicted mRNA targets. Genes correlated with these microRNAs were enriched in pathways associated with emphysema pathophysiology (for example, oxidative stress and accelerated aging). Inhibition of miR-638 expression in lung fibroblasts led to modulation of these same emphysema-related pathways. Gene targets of miR-638 in these pathways were amongst those negatively correlated with miR-638 expression in emphysema. Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression pathways related to the oxidative stress response and aging in emphysematous lung tissue and lung fibroblasts.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1165/rcmb.2008-0114oc
发表时间：
2009-03-01
影响因子：
6.4
作者：
Bhattacharya, Soumyaroop;Srisuma, Sorachai;Mariani, Thomas J.
通讯作者：
Mariani, Thomas J.
影响因子：
56.9
作者：
Farh, KKH;Grimson, A;Bartel, DP
通讯作者：
Bartel, DP
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
影响因子：
5.8
作者：
Francis SM;Larsen JE;Pavey SJ;Bowman RV;Hayward NK;Fong KM;Yang IA
通讯作者：
Yang IA