Functional genomic fabrics are remodeled in a mouse model of Chagasic cardiomyopathy and restored following cell therapy
Functional genomic fabrics are remodeled in a mouse model of Chagasic cardiomyopathy and restored following cell therapy
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DOI：
10.1016/j.micinf.2017.11.003
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发表时间：
2018-03-01
影响因子：
5.8
通讯作者：
Spray, David C.
中科院分区：
文献类型：
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作者：
Iacobas, Dumitru A.;Iacobas, Sanda;Spray, David C.
我们之前发现，在恰加斯心肌病小鼠模型中，9390个量化的独特基因中有18%受到克氏锥虫感染的显著调节。然而，骨髓源性单核细胞（mnc）治疗导致84%的转录组恢复。我们应用了新的算法来重新分析这些数据集的特定途径[恰加斯病（Chagas），心肌收缩（CMC）和趋化因子信号（CCS）]。除了单个基因的表达水平，我们还计算了基因表达变异性和每个基因与所有其他基因表达的协调。这些额外的措施揭示了CHAGAS转录物丰度控制和基因网络的变化，以及MNC处理后CHAGAS恢复的变化，这些变化无法使用限于平均表达水平的常规方法获得。此外，我们的加权通路调控分析纳入了所有受影响基因的贡献，消除了对显著调控基因的折叠变化和/或p值的任意截止标准。新的分析表明，克氏锥虫感染对CMC途径有很大的转录组影响，并引发了巨大的细胞因子信号传导。值得注意的是，MNC治疗不仅恢复了许多基因的正常表达水平，而且还恢复了大部分被感染改变的CHAGAS、CMC和CCS结构。(c) 2017巴斯德研究所。Elsevier Masson SAS出版。版权所有。
We previously found that, in a mouse model of Chagas cardiomyopathy, 18% of the 9390 quantified unigenes were significantly regulated by Trypanosoma cruzi infection. However, treatment with bone marrow-derived mononuclear cells (MNCs) resulted in 84% transcriptomic recovery. We have applied new algorithms to reanalyze these datasets with respect to specific pathways [Chagas disease (CHAGAS), cardiac muscle contraction (CMC) and chemokine signaling (CCS)]. In addition to the levels of expression of individual genes we also calculated gene expression variability and coordination of expression of each gene with all others. These additional measures revealed changes in the control of transcript abundances and gene networking in CHAGAS and restoration following MNC treatment, not accessible using the conventional approach limited to the average expression levels. Moreover, our weighted pathway regulation analysis incorporated the contributions of all affected genes, eliminating the arbitrary cut-off criteria of fold-change and/or p-value for significantly regulated genes. The new analyses revealed that T. cruzi infection had large transcriptomic consequences for the CMC pathway and triggered a huge cytokine signaling. Remarkably, MNC therapy not only restored normal expression levels of numerous genes, but it also recovered most of the CHAGAS, CMC and CCS fabrics that were altered by the infection. (c) 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.