Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks.
- Authors
- Lim, Yolpanhchana; Beane-Ebel, Jennifer E; Tanaka, Yoshiaki; Ning, Boting; Husted, Christopher R; Henderson, David C; Xiang, Yangfei; Park, In-Hyun; Farrer, Lindsay A; Zhang, Huiping
- Year
- 2021
- Journal
- Translational psychiatry
- PMID
- 34601489
- DOI
- 10.1038/s41398-021-01635-w
- PMCID
- PMC8487426
Transcriptomic changes in specific brain regions can influence the risk of alcohol use disorder (AUD), but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA-mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control European Australians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P < 0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P < 0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA-mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA-mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA-mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control European Australians. Some of the AUD-associated miRNA-mRNA regulatory networks were confirmed. In addition, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with or without ethanol exposure, and ethanol-influenced miRNA-mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA-mRNA regulatory networks might contribute to AUD development.
Volcano plots displaying differentially expressed miRNAs in eight regions of postmortem brains of subjects with alcohol use disorder (AUD) (the Set 1 sample).The vertical axis (y-axis) corresponds to the negative log10 of the P-value, and the horizontal axis (x-axis) displays the log2 of fold changes (FC). The red dots represent upregulated miRNAs (log2FC > 1.0 & P < 0.05) and the green dots represent downregulated miRNAs (log2FC < −1.0 & P < 0.05). The horizontal line shows the P-value cutoff (P = 0.05) with points above the line having the P-value <0.05 and points below the line having the P-value >0.05. The two vertical lines indicate 2-fold changes. AMY amygdala, CN caudate nucleus, CRB cerebellum, HIPPO hippocampus, NAc nucleus accumbens, PFC prefrontal cortex, PUT putamen, VTA ventral tegmental area.
Volcano plots displaying differentially expressed mRNAs in eight regions of postmortem brains of subjects with alcohol use disorder (AUD) (the Set 1 sample).The vertical axis (y-axis) corresponds to the negative log10 of the P-value, and the horizontal axis (x-axis) displays the log2 of fold changes (FC). The red dots represent upregulated mRNAs (log2FC > 1.0 & P < 0.05) and the green dots represent downregulated mRNAs (log2FC < −1.0 & P < 0.05). The horizontal line shows the P-value cutoff (P = 0.05 or 0.01) with points above the line having the P-value <0.05 or 0.01 and points below the line having the P-value >0.05 or 0.01. The two vertical lines indicate 2-fold changes. AMY amygdala, CN caudate nucleus, CRB cerebellum, HIPPO hippocampus, NAc nucleus accumbens, PFC prefrontal cortex, PUT putamen, VTA ventral tegmental area.
DIANA-mirPath KEGG pathway enrichment analysis of mRNAs potentially targeted by 19 differentially expressed miRNAs (absolute FC > 2.0 & P < 0.05) identified in one or multiple brain regions of subjects with alcohol use disorder (AUD) (the Set 1 sample).Numbers in parentheses: the number of differentially expressed miRNAs (absolute FC > 2.0 & P < 0.05) and the number of predicted target mRNAs involved in specific pathways. KEGG pathways with enrichment P values <10−4 (or –log10P > 4.0) are listed.
Alcohol use disorder (AUD)-associated miRNA–mRNA regulatory networks in the amygdala (AMY), the caudate nucleus (CN), the cerebellum (CRB), and the hippocampus (HIP) of AUD subjects (the Set 1 sample).CP: Canonical pathways potentially regulated by differentially expressed [absolute fold-change (FC) > 1.3 & P < 0.05] and negatively correlated miRNA–mRNA pairs identified in each brain region were defined using the Ingenuity Pathway Analysis (IPA) miRNA Target Filter function. miRNAs and mRNAs in red symbols: upregulated in AUD patients; miRNAs and mRNAs in green symbols: downregulated in AUD patients.
Alcohol use disorder (AUD)-associated miRNA–mRNA regulatory networks in the nucleus accumbens (NAc), the prefrontal cortex (PFC), the putamen (PUT), and the ventral tegmental area (VTA) of AUD subjects (the Set 1 sample).CP: Canonical pathways potentially regulated by differentially expressed [absolute fold-change (FC) > 1.3 & P < 0.05] and negatively correlated miRNA–mRNA pairs identified in each brain region were defined using the Ingenuity Pathway Analysis (IPA) miRNA Target Filter function. miRNAs and mRNAs in red symbols: upregulated in AUD patients; miRNAs and mRNAs in green symbols: downregulated in AUD patients.
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