Shaanxi Key Laboratory for Network Computing and Security Technology, School of Computer Science and Engineering, Xi'an University of Technology, Xi'an, 710048, Shaanxi, China.
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St., Suite 820, Houston, TX, 77030, USA.
BMC Med Genomics. 2019 Jan 31;12(Suppl 1):16. doi: 10.1186/s12920-018-0458-3.
Cleft lip (CL) is one of the most common congenital birth defects with complex etiology. While genome-wide association studies (GWAS) have made significant advances in our understanding of mutations and their related genes with potential involvement in the etiology of CL, it remains unknown how these genes are functionally regulated and interact with each other in lip development. Currently, identifying the disease-causing genes in human CL is urgently needed. So far, the causative CL genes have been largely undiscovered, making it challenging to design experiments to validate the functional influence of the mutations identified from large genomic studies such as CL GWAS.
Transcription factors (TFs) and microRNAs (miRNAs) are two important regulators in cellular system. In this study, we aimed to investigate the genetic interactions among TFs, miRNAs and the CL genes curated from the previous studies. We constructed miRNA-TF co-regulatory networks, from which the critical regulators as putative drivers in CL were examined. Based on the constructed networks, we identified ten critical hub genes with prior evidence in CL. Furthermore, the analysis of partitioned regulatory modules highlighted a number of biological processes involved in the pathology of CL, including a novel pathway "Signaling pathway regulating pluripotency of stem cells". Our subnetwork analysis pinpointed two candidate miRNAs, hsa-mir-27b and hsa-mir-497, activating the Wnt pathway that was associated with CL. Our results were supported by an independent gene expression dataset in CL.
This study represents the first regulatory network analysis of CL genes. Our work presents a global view of the CL regulatory network and a novel approach on investigating critical miRNAs, TFs and genes via combinatory regulatory networks in craniofacial development. The top genes and miRNAs will be important candidates for future experimental validation of their functions in CL.
唇裂（CL）是最常见的先天性出生缺陷之一，具有复杂的病因。虽然全基因组关联研究（GWAS）在我们理解潜在参与 CL 病因的突变及其相关基因方面取得了重大进展，但这些基因如何在唇发育过程中被功能调控以及相互作用仍不清楚。目前，迫切需要鉴定人类 CL 中的致病基因。到目前为止，导致 CL 的致病基因在很大程度上尚未被发现，这使得难以设计实验来验证从 CL GWAS 等大型基因组研究中鉴定出的突变的功能影响。
转录因子（TFs）和 microRNAs（miRNAs）是细胞系统中的两个重要调控因子。在这项研究中，我们旨在研究 TF、miRNAs 与之前研究中从 CL 中鉴定出的 CL 基因之间的遗传相互作用。我们构建了 miRNA-TF 共调控网络，从中检查了 CL 中的关键调控因子作为潜在驱动因素。基于构建的网络，我们鉴定了十个具有 CL 先前证据的关键枢纽基因。此外，分区调控模块的分析突出了涉及 CL 病理学的多个生物学过程，包括“调控干细胞多能性的信号通路”这一 novel 通路。我们的子网分析确定了两个候选 miRNA，hsa-mir-27b 和 hsa-mir-497，它们激活了与 CL 相关的 Wnt 通路。我们的结果得到了 CL 中独立基因表达数据集的支持。
这项研究代表了对 CL 基因的首次调控网络分析。我们的工作呈现了 CL 调控网络的全局视图，以及通过颅面发育中的组合调控网络研究关键 miRNA、TF 和基因的新方法。顶级基因和 miRNA 将是未来验证其在 CL 中功能的重要候选者。
