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 rema...

Full description

Bibliographic Details
Main Authors: Aimin Li, Guimin Qin, Akiko Suzuki, Mona Gajera, Junichi Iwata, Peilin Jia, Zhongming Zhao
Format: Article
Language:English
Published: BMC 2019-01-01
Series:BMC Medical Genomics
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12920-018-0458-3
id doaj-00a0cff2765f4597b235c5522a66194f
record_format Article
spelling doaj-00a0cff2765f4597b235c5522a66194f2021-04-02T05:53:53ZengBMCBMC Medical Genomics1755-87942019-01-0112S111913210.1186/s12920-018-0458-3Network-based identification of critical regulators as putative drivers of human cleft lipAimin Li0Guimin Qin1Akiko Suzuki2Mona Gajera3Junichi Iwata4Peilin Jia5Zhongming Zhao6Shaanxi Key Laboratory for Network Computing and Security Technology, School of Computer Science and Engineering, Xi’an University of TechnologyCenter for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at HoustonDepartment of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at HoustonDepartment of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at HoustonDepartment of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at HoustonCenter for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at HoustonCenter for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at HoustonAbstract 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.http://link.springer.com/article/10.1186/s12920-018-0458-3Cleft lipFeed forward loopRegulatory networkDisease-causing genemicroRNATranscription factor
collection DOAJ
language English
format Article
sources DOAJ
author Aimin Li
Guimin Qin
Akiko Suzuki
Mona Gajera
Junichi Iwata
Peilin Jia
Zhongming Zhao
spellingShingle Aimin Li
Guimin Qin
Akiko Suzuki
Mona Gajera
Junichi Iwata
Peilin Jia
Zhongming Zhao
Network-based identification of critical regulators as putative drivers of human cleft lip
BMC Medical Genomics
Cleft lip
Feed forward loop
Regulatory network
Disease-causing gene
microRNA
Transcription factor
author_facet Aimin Li
Guimin Qin
Akiko Suzuki
Mona Gajera
Junichi Iwata
Peilin Jia
Zhongming Zhao
author_sort Aimin Li
title Network-based identification of critical regulators as putative drivers of human cleft lip
title_short Network-based identification of critical regulators as putative drivers of human cleft lip
title_full Network-based identification of critical regulators as putative drivers of human cleft lip
title_fullStr Network-based identification of critical regulators as putative drivers of human cleft lip
title_full_unstemmed Network-based identification of critical regulators as putative drivers of human cleft lip
title_sort network-based identification of critical regulators as putative drivers of human cleft lip
publisher BMC
series BMC Medical Genomics
issn 1755-8794
publishDate 2019-01-01
description 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.
topic Cleft lip
Feed forward loop
Regulatory network
Disease-causing gene
microRNA
Transcription factor
url http://link.springer.com/article/10.1186/s12920-018-0458-3
work_keys_str_mv AT aiminli networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
AT guiminqin networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
AT akikosuzuki networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
AT monagajera networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
AT junichiiwata networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
AT peilinjia networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
AT zhongmingzhao networkbasedidentificationofcriticalregulatorsasputativedriversofhumancleftlip
_version_ 1724172147263275008