Inferring novel lncRNA associated with Ventricular septal defect by DNA methylation interaction network

Abstract

Ventricular septal defect (VSD) is one of the most common types of congenital heart disease. To find more and more molecular alteration is conducive to explore the mechanism and biomarker in VSD. Herein we devised a predictive strategy to uncover novel lncRNA of VSD integrating DNA methylation, gene expression and lncRNA expression of early embryo and VSD by profiles from GEO database. In totally, 175 lncRNAs, 7290 genes and 3002 DNA methylation genes were obtained by logistic regression analysis associated with embryonic development. Moreover, 7304 DMGs were significant differential methylated by Wilcoxon rank test and Students test in VSD. We constructed the lncRNA-mRNA co-expression network in embryo (LMCNe). Then, a reconstructed co-expression weighted network (RCWN) was built integrated LMCNe and the DNA methylation associated network (DMAN) based on the correlation of the DNA methylation level and protein interaction network between embryonic development and VSD. We extracted top 10 lncRNAs with higher score performing DRaWR from the weight network, which as potential VSD related lncRNAs. Six lncRNAs showed a high level of expression in the heart tissue recorded in the NONOCOND database. Furthermore, associated lncRNA genes DCAF8L1, NIT1, SH2D7 and DOCK9-AS2 in validated samples showed a prominently association with VSD. These outcomes provide a reference for lncRNA involved in VSD initialization and a new insight for studies of VSD-associated lncRNAs. Author SummaryVentricular septal defect (VSD) is one of the most common types of congenital heart disease and has a high mortality rate in infants. Many molecular markers have proved effective as biomarker in VSD like DNA methylation and lncRNA. lncRNA is a type of non-coding RNA which has important effect in regulation gene expression and disease occurrence. VSD is an embryonic stage developmental disease. Therefore we hypothesized that lncRNA which was associated with DNA methylation and mRNA in early embryonic development may also affect the occurrence of VSD. So in this work, from the perspective of embryonic development, we devised a predictive strategy to uncovering novel lncRNA of VSD. In our result, four lncRNA associated genes were found differential expressed in VSD and normal samples by qPCR validation. The identification of lncRNA associated with ventricular septal defect is beneficial to further study the mechanism of VSD from the molecular level and also provides a good molecular marker for clinical therapeutic and diagnosis. At the same time, it also provides a new insight for the researches of lncRNA associated with VSD.