Inter-tissue coexpression network analysis reveals DPP4 as an important gene in heart to blood communication.
Inter-tissue coexpression network analysis reveals DPP4 as an important gene in heart to blood communication.
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DOI：
10.1186/s13073-016-0268-1
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发表时间：
2016-02-09
期刊：
影响因子：
12.3
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Long Q;Argmann C;Houten SM;Huang T;Peng S;Zhao Y;Tu Z;GTEx Consortium;Zhu J
组织间分子相互作用对多细胞生物体中生物系统的功能和行为至关重要，但缺乏对组织间相互作用的系统研究。此外，现有的组织间相互作用的研究是基于直接的基因表达相关性，这不能区分由于共同的遗传结构与生物化学或组织之间的分子信号交换的相关性。我们开发了一种新的策略来研究组织间的相互作用，通过消除基因表达的遗传调控（遗传去相关）的影响。我们将我们的方法应用于基因型-组织表达（GTEx）项目中9种人体组织的基因表达综合图谱，以生成新的遗传去相关组织间网络。由此，我们推导出了在组织间相互作用中重要的基因模块，这些基因模块可能是由生物信号交换而不是它们共同的遗传基础驱动的。重要的是，我们强调了组织之间的通信，并阐明了一种组织中的基因活性诱导其他组织中的基因表达变化。我们揭示了全球单向组织间协调的特定生物途径，如蛋白质合成。使用我们的数据，我们强调了一个临床相关的例子，其中心脏的DPP 4表达与全血增殖的基因表达特征相协调，可能影响外周干细胞动员。我们还发现，心脏中特征不明显的FOCAD表达与肺中的蛋白质生物合成过程相关。总之，这是人类多组织网络的第一个资源，使分子组织间相互作用的调查。有了这些网络，我们可以系统地设计出同时针对多个组织的联合疗法，或者确定药物在其他组织中的潜在副作用。本文的在线版本（doi：10.1186/s13073-016-0268-1）包含补充材料，可供授权用户使用。
Inter-tissue molecular interactions are critical to the function and behavior of biological systems in multicellular organisms, but systematic studies of interactions between tissues are lacking. Also, existing studies of inter-tissue interactions are based on direct gene expression correlations, which can’t distinguish correlations due to common genetic architectures versus biochemical or molecular signal exchange between tissues. We developed a novel strategy to study inter-tissue interaction by removing effects of genetic regulation of gene expression (genetic decorrelation). We applied our method to the comprehensive atlas of gene expression across nine human tissues in the Genotype-Tissue Expression (GTEx) project to generate novel genetically decorrelated inter-tissue networks. From this we derived modules of genes important in inter-tissue interactions that are likely driven by biological signal exchange instead of their common genetic basis. Importantly we highlighted communication between tissues and elucidated gene activities in one tissue inducing gene expression changes in others. We reveal global unidirectional inter-tissue coordination of specific biological pathways such as protein synthesis. Using our data, we highlighted a clinically relevant example whereby heart expression of DPP4 was coordinated with a gene expression signature characteristic for whole blood proliferation, potentially impacting peripheral stem cell mobilization. We also showed that expression of the poorly characterized FOCAD in heart correlated with protein biosynthetic processes in the lung. In summary, this is the first resource of human multi-tissue networks enabling the investigation of molecular inter-tissue interactions. With the networks in hand, we may systematically design combination therapies that simultaneously target multiple tissues or pinpoint potential side effects of a drug in other tissues. The online version of this article (doi:10.1186/s13073-016-0268-1) contains supplementary material, which is available to authorized users.