A Novel Transcriptome Integrated Network Approach Identifies the Key Driver lncRNA Involved in Cell Cycle With Chromium (VI)-Treated BEAS-2B Cells.

Pai Zheng,Tiancheng Wang,Zhangjian Chen,Zengmiao Wang,Changmao Long,Feizai Ha,Guang Jia,Di Zhou,Yulin Kang,Huimin Feng,Shuo Han,Guiping Hu

doi:10.3389/fgene.2020.597803

Abstract

Hexavalent chromium [Cr(VI)] is a well-known occupational carcinogen, but the mechanisms contributing to DNA damage and cell cycle alternation have not been fully characterized. To study the dose-response effects of Cr(VI) on transcription, we exposed BEAS-2B cells to Cr(VI) at concentrations of 0.2, 0.6, and 1.8 μmol/L for 24 h. Here, we identified 1,484 differentially expressed genes (DEGs) in our transcript profiling data, with the majority of differentially expressed transcripts being downregulated. Our results also showed that these DEGs were enriched in pathways associated with the cell cycle, including DNA replication, chromatin assembly, and DNA repair. Using the differential expressed genes related to cell cycle, a weighted gene co-expression network was constructed and a key mRNA-lncRNA regulation module was identified under a scale-free network with topological properties. Additionally, key driver analysis (KDA) was applied to the mRNA-lncRNA regulation module to identify the driver genes. The KDA revealed that ARD3 (FDR = 1.46 × 10–22), SND1 (FDR = 5.24 × 10–8), and lnc-DHX32-2:1 (FDR = 1.43 × 10–17) were particularly highlighted in the category of G2/M, G1/S, and M phases. Moreover, several genes we identified exhibited great connectivity in our causal gene network with every key driver gene, including CDK14, POLA1, lnc-NCS1-2:1, and lnc-FOXK1-4:1 (all FDR < 0.05 in those phases). Together, these results obtained using mathematical approaches and bioinformatics algorithmics might provide potential new mechanisms involved in the cytotoxicity induced by Cr.

Highlights

Inhalation exposure to hexavalent chromium [Cr(VI)] has been recognized as a significant occupational carcinogen according to the final document from the National Institute for Occupational Safety and Health (NIOSH) (NOISH, 2008)
To fully characterize the regulation pattern between mRNA and long non-coding RNAs (lncRNAs), 18833 mRNA and 68104 lncRNA were considered in this study
A relatively lower number of differentially expressed genes was observed in the middle (129) (Figures 1A,C) and low dose (17) groups compared with normal cultured cells

Summary

Introduction

From 2006 to 2010, the potential mechanisms of Cr(VI) carcinogenesis in lung cells were extensively published, and the main hypothesis was related to genomic instability (Holmes et al, 2008), including microsatellite instability (Hirose et al, 2002; Takahashi et al, 2005), numerical chromosome instability (Xie et al, 2005), and consequences of the imbalance between cellular damage and repair systems (Yao et al, 2008). MiRNA studies related to Cr were introduced into the field of environmental toxicology, and they aimed to elucidate the mechanisms of lung cancer induced by Cr (He et al, 2013; Li et al, 2014). Over the last 4 years, miRNA-related research has been a topic of high interest and has recently received increasing attention, especially topics related to DNA repair (Li et al, 2016) or glycolipid metabolism (Zhang et al, 2018)

Methods

Results

Conclusion