Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis.
Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis.
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DOI：
10.1186/s12915-022-01447-4
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发表时间：
2022-11-11
期刊：
影响因子：
5.4
通讯作者：
Suzuki HI
中科院分区：
文献类型：
--
作者：
Kitai H;Kato N;Ogami K;Komatsu S;Watanabe Y;Yoshino S;Koshi E;Tsubota S;Funahashi Y;Maeda T;Furuhashi K;Ishimoto T;Kosugi T;Maruyama S;Kadomatsu K;Suzuki HI
多个microRNA（miRNAs）的组合基因调控是广泛的，并且紧密间隔的靶位点通常协同作用以实现更强的抑制（“邻近”miRNA共靶向）。虽然miRNA共靶位点被认为是更保守的，并参与发育控制，但miRNA共靶的病理意义仍然难以捉摸。在这里，我们报告了系统性红斑狼疮（SLE）炎症的组合miRNA调控的致病影响。在SLE小鼠模型中，我们鉴定了两种miRNA，miR-128和miR-148 a，在浆细胞样树突状细胞中通过TLR 7刺激的下调。使用人类细胞系的功能分析表明，miR-128和miR-148 a通过广泛重叠的靶位点（“种子重叠”miRNA共靶向）相加靶向KLF 4并抑制炎症反应。在转录组水平上，“种子重叠”miRNA共靶向增加了对两种miRNA下调的敏感性，这与两种miRNA的相加而非合作募集一致。系统表征进一步揭示了广泛的“种子重叠”是广泛保守的miRNA中的普遍特征。广泛保守的miRNA的高度保守的靶位点主要分为两类-真兽目哺乳动物和从人类到腔棘鱼的保守位点，后者包括KLF 4-cotargeting位点，与“种子重叠”和“邻居”miRNA cotargeting具有更强的关联。此外，高度保守的miRNA靶类别具有更高的单倍不足基因的概率。我们的研究共同表明了miRNA共同靶向的不同模式的复杂性以及它们在人类疾病中的扰动的重要性。在线版本包含补充材料，可通过10.1186/s12915-022-01447-4获得。
Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression (“neighborhood” miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites (“seed overlap” miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, “seed overlap” miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive “seed overlap” is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes—those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both “seed overlap” and “neighborhood” miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases. The online version contains supplementary material available at 10.1186/s12915-022-01447-4.
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影响因子：
30.5
作者：
Gonzalez-Martin A;Adams BD;Lai M;Shepherd J;Salvador-Bernaldez M;Salvador JM;Lu J;Nemazee D;Xiao C
通讯作者：
Xiao C
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
7
作者：
Cherone, Jennifer M.;Jorgji, Vjola;Burge, Christopher B.
通讯作者：
Burge, Christopher B.
影响因子：
13.3
作者：
Davison, Laura M.;Jorgensen, Trine N.
通讯作者：
Jorgensen, Trine N.
影响因子：
4.5
作者：
Huang N;Lee I;Marcotte EM;Hurles ME
通讯作者：
Hurles ME