Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition.
Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition.
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DOI：
10.1016/j.molcel.2014.09.018
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发表时间：
2014-11-06
期刊：
影响因子：
16
通讯作者：
Sharp, Phillip A.
中科院分区：
文献类型：
--
作者：
Bosson, Andrew D.;Zamudio, Jesse R.;Sharp, Phillip A.
miRNA调控的基因网络中的靶标竞争（ceRNA串扰）已被提出影响生物系统。为了评估靶标竞争，我们对两种细胞类型中的miRNA网络进行了表征和定量。Argonaute iCLIP揭示了高亲和力至低亲和力miRNA靶标的分级结合是体内活性的关键特征。细胞miRNA和mRNA/ncRNA靶池水平的定量表明miRNA：靶池比率和亲和力分配的靶池准确预测体内Ago结合谱和miRNA对靶竞争的敏感性。使用单细胞报告基因，我们直接测试预测，并估计约3,000个额外的高亲和力靶位点可以影响具有低内源性miRNA：靶比的活性miRNA家族，如miR-92/25。相比之下，高表达的miR-294和let-7家族对近10，000个位点的增加不敏感。这些结果显示了基于内源性miRNA：靶池比率的不同易感性，并为体内ceRNA竞争提供了生理背景。
Target competition (ceRNA crosstalk) within miRNA-regulated gene networks has been proposed to influence biological systems. To assess target competition, we characterize and quantitate miRNA networks in two cell types. Argonaute iCLIP reveals that hierarchical binding of high- to low-affinity miRNA targets is a key characteristic of in vivo activity. Quantification of cellular miRNA and mRNA/ncRNA target pool levels indicates that miRNA:target pool ratios and an affinity partitioned target pool accurately predict in vivo Ago binding profiles and miRNA susceptibility to target competition. Using single-cell reporters, we directly test predictions and estimate that ~3,000 additional high-affinity target sites can affect active miRNA families with low endogenous miRNA:target ratios, such as miR-92/25. In contrast, the highly expressed miR-294 and let-7 families are not susceptible to increases of nearly 10,000 sites. These results show differential susceptibility based on endogenous miRNA:target pool ratios and provide a physiological context for ceRNA competition in vivo.
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