Single Nucleotide Polymorphisms in Transcriptional Regulatory Elements Mediates Dilated Cardiomyopathy
Objective To explore the association between single nucleotide polymorphisms in transcriptional regulatory elements of human genome and the pathogenesis of dilated cardiomyopathy(DCM)as well as the potential pathogenic mechanism.Methods The expression quantitative trait locus(eQTL)data of cardiac tissue was combined with the H3K27ac histone-modified ChIP-seq data of 50 DCM patients to identify single nucleotide mutations located in transcriptional regulatory elements.Based on the selected single nucleotide mutations,the associated genes with altered expression levels were identified,and the potential pathogenic genes of DCM were further explored.Finally,the gene functional network was constructed.Results After intersection of heart tissue eQTL database with H3K27ac ChIP-seq data of patients with DCM,317 single nucleotide mutation sites located in the promoter regions of the patient genome and 239 single nucleotide mutation sites located in the enhancer regions were identified.A total of 556 genes associated with these mutations were predicted by the eQTL database to have altered expression levels upon occurrence of these single nucleotide mutations.Gene function analysis showed that these genes were significantly enriched in many biological processes such as endothelial cell migration,histone acetylation modification,actin cytoskeleton recombination,and cortical microtubule organization.By comparing the RNA-seq data of patients with DCM and healthy controls,we found that the expression levels of genes associated with single nucleotide mutations in the promoter region including TMEM30B,AEBP1,SCARA3,HSH2D,DACT2,EGR3,AC108448.2 and RP11-338N10.2 were significantly up-regulated,while HRCT1 was significantly down-regulated.The genes associated with single nucleotide mutation in enhancer region including ATP1B2 and SKAP1 were significantly up-regulated,while FER1L6,SLGLEC14 and RP11-231C14.6 were significantly down-regulated(Padj＜0.01,|Log2FoldChange|＞1).Combined with KEGG pathway analysis,core genes possess mutations in promoters and involves in many pathways were found which included PIK3CD,SREBF1,SOS1,SEH1L,WDR24,NPRL3 and RPS6.Core genes possess mutations in enhancers were also found which included TRPV4,EZR,EFNB2 and ANXA1.These genes were involved in multiple biological processes or signaling pathways.Conclusion Single nucleotide mutations are associated with DCM and are broadly distributed in promoter and enhancer regions of the genome.Single nucleotide mutations may lead to changes in the expression level of associated genes,which in turn lead to dysregulation of participating biological processes and signaling pathways,and ultimately mediate the occurrence and progression of dilated cardiomyopathy.The associated genes and core associated genes predicted to change the gene expression level can be used as potential biomarkers and therapeutic targets for dilated cardiomyopathy.
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