FGD5-AS1 Is a Hub lncRNA ceRNA in Hearts With Tetralogy of Fallot Which Regulates Congenital Heart Disease Genes Transcriptionally and Epigenetically.
FGD5-AS1 Is a Hub lncRNA ceRNA in Hearts With Tetralogy of Fallot Which Regulates Congenital Heart Disease Genes Transcriptionally and Epigenetically.
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FGD5-AS1 是法洛四联症心脏中的一个枢纽 lncRNA ceRNA，可从转录和表观遗传角度调节先天性心脏病基因
DOI：
10.3389/fcell.2021.630634
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发表时间：
2021
影响因子：
5.5
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Zhang X;Gao Y;Zhang X;Zhang X;Xiang Y;Fu Q;Wang B;Xu Z
心脏发育需要强大的基因调控，而相关的干扰可能会导致先天性心脏病(CHD)。为了深入了解CHD基因表达的调控，我们通过链特异性转录分析，获得了22例法洛四联症(TOF)心脏组织中长非编码RNA(LncRNAs)和信使RNAs(MRNAs)的表达谱。利用一个基于表达相关性和验证的microRNA(MiRNA)-lncRNA-mRNA证据的因果推理框架，我们构建了由lncRNAs驱动的竞争内源RNA(CerNA)介导的网络。4个LncRNAs(FGD5-AS1、Lnc-GNB4-1、Lnc-PDK3-1和Lnc-SAMD5-1)被鉴定为网络中的中枢LncRNAs。由于FGD5-AS1的所有靶点都是CHD相关基因(NRAS、PTEN和Smad4)，因此选择FGD5-AS1进行进一步研究。FGD5-AS1和Smad4都能与hsa-miR-421结合，双荧光素酶报告基因分析证实了这一点。FGD5-AS1基因的敲除不仅显著降低PTEN和Smad4在HEK 293和胎儿心脏细胞系(CCC-HEH-2)中的表达，而且以细胞特异性的方式增加其相互作用的miRNAs的转录。除了CENA机制外，RNAseq和ATACseq结果表明，FGD5-AS1可能通过转录调控CHD相关基因而在心脏发育中发挥抑制作用。总之，我们在TOF患者的心脏组织中发现了一个由lncRNAs驱动的Cerna网络。此外，我们还证明了FGD5-AS1是TOF心脏Cerna网络中的一个中枢lncRNA，从转录和表观遗传上调节多个基因。
Heart development requires robust gene regulation, and the related disruption could lead to congenital heart disease (CHD). To gain insights into the regulation of gene expression in CHD, we obtained the expression profiles of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in 22 heart tissue samples with tetralogy of Fallot (TOF) through strand-specific transcriptomic analysis. Using a causal inference framework based on the expression correlations and validated microRNA (miRNA)–lncRNA–mRNA evidences, we constructed the competing endogenous RNA (ceRNA)-mediated network driven by lncRNAs. Four lncRNAs (FGD5-AS1, lnc-GNB4-1, lnc-PDK3-1, and lnc-SAMD5-1) were identified as hub lncRNAs in the network. FGD5-AS1 was selected for further study since all its targets were CHD-related genes (NRAS, PTEN, and SMAD4). Both FGD5-AS1 and SMAD4 could bind with hsa-miR-421, which has been validated using dual-luciferase reporter assays. Knockdown of FGD5-AS1 not only significantly reduced PTEN and SMAD4 expression in HEK 293 and the fetal heart cell line (CCC-HEH-2) but also increased the transcription of its interacted miRNAs in a cell-specific way. Besides ceRNA mechanism, RNAseq and ATACseq results showed that FGD5-AS1 might play repression roles in heart development by transcriptionally regulating CHD-related genes. In conclusion, we identified a ceRNA network driven by lncRNAs in heart tissues of TOF patients. Furthermore, we proved that FGD5-AS1, one hub lncRNA in the TOF heart ceRNA network, regulates multiple genes transcriptionally and epigenetically.
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