Journal Article

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

Suzuki, Akiko, Li, Aimin, Qin, Guimin, Gajera, Mona, Zhao, Zhongming, Jia, Peilin, Iwata, Junichi

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acids / Analysis / Binding sites / Biomedical and Life Sciences / Biomedicine / Birth defects / Cancer / Care and treatment / Cleft lip / Cleft Lip - genetics / Cleft Lip - pathology / Cleft lip/palate / Computational Biology - methods / Congenital defects / Congenital diseases / Craniofacial growth / Disease-causing gene / Etiology / Etiology (Medicine) / Feed forward loop / Gene Expression / Gene Regulatory Networks / Genes / Genetic aspects / Genetic disorders / Genomes / Genomics / Health aspects / Human Genetics / Humans / Microarrays / MicroRNA / MicroRNAs / MicroRNAs - genetics / miRNA / Motor vehicle drivers / Mutation / Novels / Pluripotency / Regulatory network / Researchers / Risk factors / Signal transduction / Stem cells / Studies / Transcription (Genetics) / Transcription factor / Transcription factors / Transcription Factors - metabolism / Wnt protein / Wnt Signaling Pathway - genetics