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实验捕获 miRNA 靶标组：基于疾病特异性 3'UTR 文库的帕金森病 miRNA 靶标组学。

Experimental capture of miRNA targetomes: disease-specific 3'UTR library-based miRNA targetomics for Parkinson's disease.

机构信息

Human Genetics, Saarland University, 66421, Homburg, Germany.

Clinical Bioinformatics, Saarland University, 66123, Saarbrücken, Germany.

出版信息

Exp Mol Med. 2024 Apr;56(4):935-945. doi: 10.1038/s12276-024-01202-5. Epub 2024 Apr 1.

DOI:10.1038/s12276-024-01202-5
PMID:38556547
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11059366/
Abstract

The identification of targetomes remains a challenge given the pleiotropic effect of miRNAs, the limited effects of miRNAs on individual targets, and the sheer number of estimated miRNA-target gene interactions (MTIs), which is around 44,571,700. Currently, targetome identification for single miRNAs relies on computational evidence and functional studies covering smaller numbers of targets. To ensure that the targetome analysis could be experimentally verified by functional assays, we employed a systematic approach and explored the targetomes of four miRNAs (miR-129-5p, miR-129-1-3p, miR-133b, and miR-873-5p) by analyzing 410 predicted target genes, both of which were previously associated with Parkinson's disease (PD). After performing 13,536 transfections, we validated 442 of the 705 putative MTIs (62,7%) through dual luciferase reporter assays. These analyses increased the number of validated MTIs by at least 2.1-fold for miR-133b and by a maximum of 24.3-fold for miR-873-5p. Our study contributes to the experimental capture of miRNA targetomes by addressing i) the ratio of experimentally verified MTIs to predicted MTIs, ii) the sizes of disease-related miRNA targetomes, and iii) the density of MTI networks. A web service to support the analyses on the MTI level is available online ( https://ccb-web.cs.uni-saarland.de/utr-seremato ), and all the data have been added to the miRATBase database ( https://ccb-web.cs.uni-saarland.de/miratbase ).

摘要

鉴于 miRNA 的多效性、miRNA 对单个靶标影响的有限性以及估计的 miRNA-靶基因相互作用 (MTI) 的数量之多（约为 44,571,700），靶标组的鉴定仍然是一个挑战。目前，单个 miRNA 的靶标组鉴定依赖于计算证据和功能研究，这些研究涵盖的靶标数量较少。为了确保靶标组分析能够通过功能测定实验进行验证，我们采用了系统的方法，通过分析与帕金森病（PD）相关的 410 个预测靶基因，探索了四个 miRNA（miR-129-5p、miR-129-1-3p、miR-133b 和 miR-873-5p）的靶标组。在进行了 13,536 次转染后，我们通过双荧光素酶报告基因测定验证了 705 个潜在 MTI 中的 442 个（62.7%）。这些分析将 miR-133b 的验证 MTI 数量增加了至少 2.1 倍，将 miR-873-5p 的验证 MTI 数量增加了最多 24.3 倍。我们的研究通过解决以下问题，为 miRNA 靶标组的实验捕获做出了贡献：i）实验验证的 MTI 与预测的 MTI 的比例，ii）与疾病相关的 miRNA 靶标组的大小，以及 iii）MTI 网络的密度。一个支持 MTI 水平分析的网络服务可在线使用（https://ccb-web.cs.uni-saarland.de/utr-seremato），所有数据都已添加到 miRATBase 数据库（https://ccb-web.cs.uni-saarland.de/miratbase）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/2b50a2042598/12276_2024_1202_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/f668c7e8ecbb/12276_2024_1202_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/211f7082e760/12276_2024_1202_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/2b50a2042598/12276_2024_1202_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/f668c7e8ecbb/12276_2024_1202_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/b65be3d4e0c6/12276_2024_1202_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/ab0bfb7c214a/12276_2024_1202_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/211f7082e760/12276_2024_1202_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbfd/11059366/2b50a2042598/12276_2024_1202_Fig5_HTML.jpg

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