AUTHOR=Gao Qing-Yuan , Zhang Hai-Feng , Chen Zhi-Teng , Li Yue-Wei , Wang Shao-Hua , Wen Zhu-Zhi , Xie Yong , Mai Jing-Ting , Wang Jing-Feng , Chen Yang-Xin 

TITLE=Construction and Analysis of a ceRNA Network in Cardiac Fibroblast During Fibrosis Based on in vivo and in vitro Data

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.503256

DOI=10.3389/fgene.2020.503256

ISSN=1664-8021

ABSTRACT=<sec><title>Aims</title><p>Activation of cardiac fibroblasts (CF) is crucial to cardiac fibrosis. We constructed a cardiac fibroblast-related competing endogenous RNA (ceRNA) network. Potential functions related to fibrosis of “hub genes” in this ceRNA network were explored.</p></sec><sec><title>Materials and Methods</title><p>The Gene Expression Omnibus database was searched for eligible datasets. Differentially expressed messenger (m)RNA (DE-mRNA) and long non-coding (lnc)RNA (DE-lncRNA) were identified. microRNA was predicted and validated. A predicted ceRNA network was constructed and visualized by Cytoscape, and ceRNA crosstalk was validated. A Single Gene Set Enrichment Analysis (SGSEA) was done, and the Comparative Toxicogenomics Database (CTD) was employed to analyze the most closely associated pathways and diseases of DE-mRNA in the ceRNA network. The functions of DE-mRNA and DE-lncRNA in the ceRNA network were validated by small interfering (si)RNA depletion.</p></sec><sec><title>Results</title><p>The GSE97358 and GSE116250 datasets (which described differentially expressed genes in human cardiac fibroblasts and failing ventricles, respectively) were used for analyses. Four-hundred-and-twenty DE-mRNA and 39 DE-lncRNA, and 369 DE-mRNA and 93 DE-lncRNA were identified, respectively, in the GSE97358 and GSE116250 datasets. Most of the genes were related to signal transduction, cytokine activity, and cell proliferation. Thirteen DE-mRNA with the same expression tendency were overlapped in the two datasets. Twenty-three candidate microRNAs were predicted and the expression of 11 were different. Only two DE-lncRNA were paired to any one of 11 microRNA. Finally, two mRNA [ADAM metallopeptidase domain 19, (<italic>ADAM19</italic>) and transforming growth factor beta induced, (<italic>TGFBI</italic>)], three microRNA (<italic>miR-9-5p</italic>, <italic>miR-124-3p</italic>, and <italic>miR-153-3p</italic>) and two lncRNA (<italic>LINC00511</italic> and <italic>SNHG15</italic>) constituted our ceRNA network. siRNA against <italic>LINC00511</italic> increased <italic>miR-124-3p</italic> and <italic>miR-9-5p</italic> expression, and decreased <italic>ADAM19</italic> and <italic>TGFBI</italic> expression, whereas siRNA against <italic>SNHG15</italic> increased <italic>miR-153-3p</italic> and decreased <italic>ADAM19</italic> expression. <italic>ADAM19</italic> and <italic>TGFBI</italic> were closely related to the TGF-β1 pathway and cardiac fibrosis, as shown by SGSEA and CTD, respectively. Depletion of two mRNA or two lncRNA could alleviate CF activation.</p></sec><sec><title>Conclusions</title><p>The CF-specific ceRNA network, including two lncRNA, three miRNA, and two mRNA, played a crucial role during cardiac fibrosis, which provided potential target genes in this field.</p></sec>