MicroRNA Networks Alter to Conform to Transcription Factor Networks Adding Redundancy and Reducing the Repertoire of Target Genes for Coordinated Regulation
MicroRNA Networks Alter to Conform to Transcription Factor Networks Adding Redundancy and Reducing the Repertoire of Target Genes for Coordinated Regulation
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DOI：
10.1093/molbev/msq231
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发表时间：
2011-01-01
影响因子：
10.7
通讯作者：
Ishida, Toshihiko
中科院分区：
文献类型：
--
作者：
Iwama, Hisakazu;Murao, Koji;Ishida, Toshihiko
转录因子（tf）和microrna （mirna）构成基因调控网络（grn）的两大层。tf和mirna协同发挥作用，但它们具有不同的分子机制和进化背景。因此，我们旨在系统地揭示TF和miRNA网络对其协调调节进化的贡献差异，重点关注复合前馈电路（cFFCs），每个电路都包含一个TF和一个miRNA。我们将124,736个人类小鼠保守的TF调控连接和34298个保守的miRNA调控连接编译成两个不同的连接矩阵。为了区分TFs和mirna对cFFC形成的贡献，我们随机化了一个基质，另一个基质保持不变，随后检测了cFFC的数量、cFFC靶向基因的数量以及cFFC与真实grn形成的冗余度。因为矩阵表示有选择性约束的网络，如果选择已经在网络上运行，支持或反对cFFC形成，cFFC网络属性的值将显著偏离随机网络的期望。由于cFFC同时包含TF和miRNA连接，部分随机化表明选择对TF和miRNA网络之间cFFC形成的影响程度存在差异。因此，我们采用每个cFFC网络属性值的偏差作为度量来估计选择对cFFC的影响程度，并比较TF和miRNA网络之间的贡献。我们发现miRNA调节网络改变了它们的结构，使它们符合稳定的TF调节网络，增加了电路冗余，并显著减少了cffc靶向基因的曲目。我们还发现，这种冗余添加作用优先归因于miRNA网络的改变。结果表明，冗余添加作用可能是许多miRNA连接存活的利基，避免了与稳定的TF调节网络的冲突。
Transcription factors (TFs) and microRNAs (miRNAs) comprise two major layers of gene regulatory networks (GRNs). TFs and miRNAs function coordinately, but they have distinct molecular mechanisms and evolutionary backgrounds. Therefore, we aimed to systematically reveal the difference in contribution between TF and miRNA networks to the evolution of their coordinated regulations by focusing on composite feedforward circuits (cFFCs) that each comprises a TF and an miRNA. We compiled 124,736 human-mouse conserved TF regulatory connections and 34,298 conserved miRNA regulatory connections into two distinct connection matrices. To differentially assess the contributions to cFFC formation of TFs and miRNAs, we randomized one matrix and kept the other unchanged and subsequently examined the number of cFFCs, the number of cFFC-targeted genes, and the redundancy formed by cFFCs in comparison with those of the real GRNs. Because the matrices represent selectively constrained networks, if selection has been operating on the networks for or against cFFC formation, the values of cFFC network properties would deviate significantly from the expectation of the randomized networks. As the cFFC includes both TF and miRNA connections, the partial randomizations indicate the extent of influence of selection on cFFC formation differentially between TF and miRNA networks. Thus, we adopted the deviation of each cFFC network property value as a measure to estimate the extent of influence of selection on cFFCs and to compare the contribution between TF and miRNA networks. We found that miRNA regulatory networks changed their configuration such that they conformed to the stable TF regulatory networks with an increased circuit redundancy and a marked reduction in the repertoire of cFFC-targeted genes. We also revealed that this redundancy-adding role is preferentially attributable to miRNA network alterations. The results indicate that the redundancy-adding role might serve as a niche for many miRNA connections to survive, avoiding conflicts with the stable TF regulatory networks.