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Network-based identification of critical regulators as putative drivers of human cleft lip.

ABSTRACT: BACKGROUND: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Li A

PROVIDER: S-EPMC6357351 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Network-based identification of critical regulators as putative drivers of human cleft lip.

Li Aimin A Qin Guimin G Suzuki Akiko A Gajera Mona M Iwata Junichi J Jia Peilin P Zhao Zhongming Z

BMC medical genomics 20190131 Suppl 1

<h4>Background</h4>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 caus ...[more]

PMID: 30704473

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Project description:BackgroundCleft lip with or without cleft palate (CL/P) is one of the most common congenital human birth defects. A combination of genetic and epidemiology studies has contributed to a better knowledge of CL/P-associated candidate genes and environmental risk factors. However, the etiology of CL/P remains not fully understood. In this study, to identify new CL/P-associated genes, we conducted an integrative analysis using our in-house network tools, dmGWAS [dense module search for Genome-Wide Association Studies (GWAS)] and EW_dmGWAS (Edge-Weighted dmGWAS), in a combination with GWAS data, the human protein-protein interaction (PPI) network, and differential gene expression profiles.ResultsA total of 87 genes were consistently detected in both European and Asian ancestries in dmGWAS. There were 31.0% (27/87) showed nominal significance with CL/P (gene-based p < 0.05), with three genes showing strong association signals, including KIAA1598, GPR183, and ZMYND11 (p < 1 × 10- 3). In EW_dmGWAS, we identified 253 and 245 module genes associated with CL/P for European ancestry and the Asian ancestry, respectively. Functional enrichment analysis demonstrated that these genes were involved in cell adhesion, protein localization to the plasma membrane, the regulation of the apoptotic signaling pathway, and other pathological conditions. A small proportion of genes (5.1% for European ancestry; 2.4% for Asian ancestry) had prior evidence in CL/P as annotated in CleftGeneDB database. Our analysis highlighted nine novel CL/P candidate genes (BRD1, CREBBP, CSK, DNM1L, LOR, PTPN18, SND1, TGS1, and VIM) and 17 previously reported genes in the top modules.ConclusionsThe genes identified through superimposing GWAS signals and differential gene expression profiles onto human PPI network, as well as their functional features, helped our understanding of the etiology of CL/P. Our multi-omics integrative analyses revealed nine novel candidate genes involved in CL/P.

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Network-based identification of critical regulators as putative drivers of human cleft lip.

Publications

Network-based identification of critical regulators as putative drivers of human cleft lip.

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