Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Shaanxi Key Laboratory for Network Computing and Security Technology, School of Computer Science and Engineering, Xi'an University of Technology, Xi'an, Shaanxi, 710048, China.
Brief Bioinform. 2020 Jul 15;21(4):1465-1478. doi: 10.1093/bib/bbz082.
Cleft palate (CP) is the second most common congenital birth defect. The etiology of CP is complicated, with involvement of various genetic and environmental factors. To investigate the gene regulatory mechanisms, we designed a powerful regulatory analytical approach to identify the conserved regulatory networks in humans and mice, from which we identified critical microRNAs (miRNAs), target genes and regulatory motifs (miRNA-TF-gene) related to CP. Using our manually curated genes and miRNAs with evidence in CP in humans and mice, we constructed miRNA and transcription factor (TF) co-regulation networks for both humans and mice. A consensus regulatory loop (miR17/miR20a-FOXE1-PDGFRA) and eight miRNAs (miR-140, miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-451a and miR-92a) were discovered in both humans and mice. The role of miR-140, which had the strongest association with CP, was investigated in both human and mouse palate cells. The overexpression of miR-140-5p, but not miR-140-3p, significantly inhibited cell proliferation. We further examined whether miR-140 overexpression could suppress the expression of its predicted target genes (BMP2, FGF9, PAX9 and PDGFRA). Our results indicated that miR-140-5p overexpression suppressed the expression of BMP2 and FGF9 in cultured human palate cells and Fgf9 and Pdgfra in cultured mouse palate cells. In summary, our conserved miRNA-TF-gene regulatory network approach is effective in detecting consensus miRNAs, motifs, and regulatory mechanisms in human and mouse CP.
腭裂（CP）是第二大常见的先天性出生缺陷。CP 的病因复杂，涉及多种遗传和环境因素。为了研究基因调控机制，我们设计了一种强大的调控分析方法，以鉴定人类和小鼠中保守的调控网络，从中我们确定了与 CP 相关的关键 microRNA（miRNA）、靶基因和调控基序（miRNA-TF-gene）。使用我们在人类和小鼠中具有 CP 证据的人工 curated 基因和 miRNA，我们构建了人类和小鼠的 miRNA 和转录因子（TF）共调控网络。我们发现了一个保守的调控环（miR17/miR20a-FOXE1-PDGFRA）和八个 miRNA（miR-140、miR-17、miR-18a、miR-19a、miR-19b、miR-20a、miR-451a 和 miR-92a）在人类和小鼠中都存在。我们研究了与 CP 关联最强的 miR-140 在人类和小鼠腭细胞中的作用。过表达 miR-140-5p，但不是 miR-140-3p，可显著抑制细胞增殖。我们进一步研究了 miR-140 过表达是否可以抑制其预测靶基因（BMP2、FGF9、PAX9 和 PDGFRA）的表达。我们的结果表明，miR-140-5p 过表达可抑制体外培养的人腭细胞中 BMP2 和 FGF9 的表达，以及体外培养的鼠腭细胞中 Fgf9 和 Pdgfra 的表达。总之，我们的保守 miRNA-TF-gene 调控网络方法可有效检测人类和小鼠 CP 中的共识 miRNA、基序和调控机制。
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