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.
| # | Section | Preview |
|---|---|---|
| 0 | Introduction | Alcohol use disorder (AUD) is characterized by uncontrolled alcohol drinking due to physical and… |
| 1 | Introduction | Studies with animal-based models and human postmortem brains have demonstrated that alcohol exposure… |
| 2 | Introduction | [13], cell adhesion [12], and neuronal apoptosis [5, 11, 12]. Differentially expressed coding genes… |
| 3 | Introduction | AUD-associated mRNA expression changes can only partially explain the molecular mechanisms of AUD.… |
| 4 | Introduction | Given that AUD is a genetically heterogeneous disorder, it is commonly agreed that multiple genes… |
| 5 | Introduction | Here, we report the first network analysis of AUD-associated brain miRNAs and mRNAs. Specifically,… |
| 6 | Materials and methods — Human postmortem brain tissues | Two sets of freshly-frozen autopsy brain tissue samples were obtained from the New South Wales Brain… |
| 7 | Materials and methods — Isolation and selection of brain tissue RNA samples for miRNA and mRNA transcriptome analysis | Total RNAs were isolated from 10 to 50 mg of postmortem brain tissue samples using the miRNeasy Mini… |
| 8 | Materials and methods — Isolation and selection of brain tissue RNA samples for miRNA and mRNA transcriptome analysis | cases and controls were matched by sex, age, RINs, and postmortem intervals (PMIs). Characteristics… |
| 9 | Materials and methods — RNA-seq analysis of miRNA and mRNA transcriptomic changes in eight brain regions of AUD subjects (192 Set 1 RNA samples) | miRNA and mRNA expression profiles of the 192 selected Set 1 RNA samples were analyzed,… |
| 10 | Materials and methods — RNA-seq analysis of miRNA and mRNA transcriptomic changes in eight brain regions of AUD subjects (192 Set 1 RNA samples) | Aligner) was 73.2%. Principal component analysis (PCA) of miRNA transcriptome data of these 192… |
| 11 | Materials and methods — RNA-seq analysis of miRNA and mRNA transcriptomic changes in eight brain regions of AUD subjects (192 Set 1 RNA samples) | Since most of the 192 selected postmortem brain RNA samples had RINs below 7 (Table S1), the KAPA… |
| 12 | Materials and methods — RNA-seq analysis of miRNA and mRNA transcriptomic changes in eight brain regions of AUD subjects (192 Set 1 RNA samples) — Microarray analysis of miRNA and mRNA transcriptomic changes in six brain regions of AUD subjects (96 Set 2 RNA samples) | For miRNA transcriptome analysis, the Affymetrix GeneChipTM miRNA4.0 array (Affymetrix, Santa Clara,… |
| 13 | Materials and methods — RNA-seq analysis of miRNA and mRNA transcriptomic changes in eight brain regions of AUD subjects (192 Set 1 RNA samples) — Microarray analysis of miRNA and mRNA transcriptomic changes in six brain regions of AUD subjects (96 Set 2 RNA samples) | Console (EC) software (v1.4.1) with the “MicroRNA Arrays – RMA (robust multi-array average) +… |
| 14 | Materials and methods — RNA-seq analysis of miRNA and mRNA transcriptomic changes in eight brain regions of AUD subjects (192 Set 1 RNA samples) — Microarray analysis of miRNA and mRNA transcriptomic changes in six brain regions of AUD subjects (96 Set 2 RNA samples) | For mRNA transcriptome analysis, the Affymetrix ClariomTM D human array (Affymetrix, Santa Clara,… |
| 15 | Materials and methods — Differentiation of hESCs into cortical interneurons and analysis of ethanol-induced miRNA and mRNA transcriptomic changes by RNA-seq | hESC-derived cortical interneurons were used as cellular models for analyzing ethanol-induced miRNA… |
| 16 | Materials and methods — Differentiation of hESCs into cortical interneurons and analysis of ethanol-induced miRNA and mRNA transcriptomic changes by RNA-seq | USA) and 1 μM of purmorphamine (Stemgent, Cambridge, MA, USA), and the medium was changed every… |
| 17 | Materials and methods — Differentiation of hESCs into cortical interneurons and analysis of ethanol-induced miRNA and mRNA transcriptomic changes by RNA-seq | hESC-derived cortical interneurons were then cultured in the neuronal maturation media containing… |
| 18 | Materials and methods — Differentiation of hESCs into cortical interneurons and analysis of ethanol-induced miRNA and mRNA transcriptomic changes by RNA-seq | miRNA transcriptomes of hESC-derived neurons (exposed or unexposed to ethanol) were profiled by… |
| 19 | Materials and methods — Differentiation of hESCs into cortical interneurons and analysis of ethanol-induced miRNA and mRNA transcriptomic changes by RNA-seq | mRNA-seq was applied to profile the mRNA transcriptome of hESC-derived cortical interneurons since… |
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