Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
Development. 2020 Dec 24;147(24):dev192948. doi: 10.1242/dev.192948.
Craniofacial development is regulated through dynamic and complex mechanisms that involve various signaling cascades and gene regulations. Disruption of such regulations can result in craniofacial birth defects. Here, we propose the first developmental stage-specific network approach by integrating two crucial regulators, transcription factors (TFs) and microRNAs (miRNAs), to study their co-regulation during craniofacial development. Specifically, we used TFs, miRNAs and non-TF genes to form feed-forward loops (FFLs) using genomic data covering mouse embryonic days E10.5 to E14.5. We identified key novel regulators (TFs Foxm1, Hif1a, Zbtb16, Myog, Myod1 and Tcf7, and miRNAs miR-340-5p and miR-129-5p) and target genes (, and ) expression of which changed in a developmental stage-dependent manner. We found that the Wnt-FoxO-Hippo pathway (from E10.5 to E11.5), tissue remodeling (from E12.5 to E13.5) and miR-129-5p-mediated regulation (from E10.5 to E14.5) might play crucial roles in craniofacial development. Enrichment analyses further suggested their functions. Our experiments validated the regulatory roles of miR-340-5p and Foxm1 in the Wnt-FoxO-Hippo subnetwork, as well as the role of miR-129-5p in the miR-129-5p- subnetwork. Thus, our study helps understand the comprehensive regulatory mechanisms for craniofacial development.
颅面发育受涉及多种信号级联和基因调控的动态复杂机制调控。这些调控的破坏会导致颅面出生缺陷。在这里,我们提出了第一个发育阶段特异性网络方法,通过整合两个关键调节因子(转录因子(TFs)和 microRNAs(miRNAs))来研究它们在颅面发育过程中的共同调节。具体来说,我们使用 TFs、miRNAs 和非 TF 基因,使用涵盖小鼠胚胎第 10.5 天至第 14.5 天的基因组数据,形成前馈回路(FFLs)。我们确定了关键的新调节因子(TFs Foxm1、Hif1a、Zbtb16、Myog、Myod1 和 Tcf7,以及 miRNAs miR-340-5p 和 miR-129-5p)及其靶基因(,和)的表达,其表达随发育阶段的变化而变化。我们发现,Wnt-FoxO-Hippo 通路(从 E10.5 到 E11.5)、组织重塑(从 E12.5 到 E13.5)和 miR-129-5p 介导的 调节(从 E10.5 到 E14.5)可能在颅面发育中起关键作用。富集分析进一步表明了它们的功能。我们的实验验证了 miR-340-5p 和 Foxm1 在 Wnt-FoxO-Hippo 子网络中的调节作用,以及 miR-129-5p 在 miR-129-5p-子网络中的作用。因此,我们的研究有助于理解颅面发育的综合调控机制。
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