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Biological function and mechanism of circRNA in the occurrence and development of hepatocellular carcinoma

ABSTRACT: Biological function and mechanism of circRNA in the occurrence and development of hepatocellular carcinoma

PROVIDER: PRJNA892102 | ENA |

REPOSITORIES: ENA

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Project description:Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular-RNA (circRNA) are noncoding RNA that form closed-looped structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in nucleus accumbens (NAc) from 32 AD matched cases/controls. Significant circRNA (unadj. p≤0.05) were identified via regression and clustered in circRNA networks via WGCNA. CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. MatrixeQTL was used to identify eQTLs affecting circRNA expression. Genomic enrichment was used to detect overlap between eQTLs and recent GWAS of substance abuse. Significant circRNAs (N=542) clustered in 9 significant AD modules (FWER p≤0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA:miRNA:mRNA interactions (FDR≤0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we identified 96 significant circRNA eQTLs (unadj. p≤0.002), showing significant enrichment within recent alcohol use disorder (AUD) and smoking GWAS. To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNA impact mRNA expression by interacting with miRNA in the NAc of AD subjects. We further identify genetic variants affecting circRNA expression impacting potential miRNA and mRNA interactions. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.

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Biological function and mechanism of circRNA in the occurrence and development of hepatocellular carcinoma

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