Alcohol use disorder causes global changes in splicing in the human brain.
- Authors
- Van Booven, Derek; Mengying Li; Sunil Rao, J; Blokhin, Ilya O; Dayne Mayfield, R; Barbier, Estelle; Heilig, Markus; Wahlestedt, Claes
- Year
- 2021
- Journal
- Translational psychiatry
- PMID
- 33414398
- DOI
- 10.1038/s41398-020-01163-z
- PMCID
- PMC7790816
Alcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.
Differentially expressed genes in brain regions of patients with alcohol use disorder.SFC superior frontal cortex, NA nucleus accumbens, BLA basolateral amygdala, CNA central nucleus of the amygdala.
LLM interpretation
This bar chart displays the number of altered genes across four brain regions: superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). The y-axis represents the "Number of Altered Genes," ranging from 0 to 150. The BLA shows the highest number of altered genes (approximately 100), followed by the CNA, with the SFC and NA showing the lowest counts.
Mis-splicing patterns in brain regions of patients with alcohol use disorder.SFC superior frontal cortex, NA nucleus accumbens, BLA basolateral amygdala, CNA central nucleus of the amygdala; 5′-SS alternative 5′ splice site, IR intron retention, 3′-SS alternative 3′ splice site, ES exon skipping, MEE mutually exclusive exons.
LLM interpretation
This figure consists of four horizontal bar charts showing the number of mis-splicing events across four brain regions: SFC, NA, BLA, and CNA. In all regions, exon skipping (ES, green bar) is the most frequent event, followed by mutually exclusive exons (MEE, black bar). The x-axis represents the "Number of Events" (0–1000), while the y-axis lists five splicing types: 5′-SS, IR, 3′-SS, ES, and MEE.
Expression of small nuclear RNAs (snRNAs) in the brain in alcohol use disorder (AUD).SFC superior frontal cortex, NA nucleus accumbens, BLA basolateral amygdala, CNA central nucleus of the amygdala. Two-tailed Student’s t test was used to compare the expression of snRNAs between two groups within each region. To compare the means between multiple groups, we employed two-way ANOVA which allows testing for interactions between two factors.
LLM interpretation
This figure consists of four bar charts showing the relative expression of four small nuclear RNAs (snU1, snU4, snU6, and snU7) in four brain regions: the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). Each chart compares a Control group (black bars) to an Alcohol Use Disorder (AUD) group (green bars). While some minor variations in expression are visible—such as an increase in snU1 in the NA and a decrease in snU1 in the CNA for the AUD group—there are no statistical significance markers indicated on the plots.
Expression of heat shock protein family A (Hsp70) member 6 (HSPA6) in the brain regions of patients with alcohol use disorder (AUD).SFC superior frontal cortex, NA nucleus accumbens, BLA basolateral amygdala, CNA central nucleus of the amygdala. Two-tailed Student’s t test was used to compare the expression of snRNAs between two groups within each region. *P < 0.05.
LLM interpretation
This bar chart shows the relative expression of HSPA6 across four brain regions (SFC, NA, BLA, and CNA) in Control (black) and AUD (green) groups. HSPA6 expression is significantly higher in the AUD group compared to the Control group in the SFC, BLA, and CNA regions, as indicated by asterisks (*P < 0.05). No significant difference is observed in the NA region.
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| Central amygdala single-nucleus atlas reveals chromatin and gene transcription dynamics in human alcohol use disorder. | Lee CY et al. | — | 2026 | → |
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| Alternative splicing in addiction. | Bhatnagar A et al. | — | 2025 | → |
| Changes in RNA Splicing: A New Paradigm of Transcriptional Responses to Probiotic Action in the Mammalian Brain. | Yue X et al. | — | 2025 | → |
| Dysregulation of Central-Medial Amygdala Histone Modifiers in Preclinical Models of Ethanol Exposure. | Lamb KA et al. | — | 2025 | → |
| Gene expression differences associated with alcohol use disorder in human brain. | Willis C et al. | — | 2025 | → |
| Noncoding RNA and Alcohol Use Disorder: A Scoping Review of Current Research and Knowledge Gaps. | Upreti D et al. | — | 2025 | → |
| SNORD3C, a blood biomarker associated to suicide attempts in patients with anorexia nervosa. | Verebi C et al. | — | 2025 | → |
| AUD in perspective. | de Bejczy A et al. | — | 2024 | → |
| It is not just about transcription: involvement of brain RNA splicing in substance use disorders. | Carvalho L et al. | — | 2024 | → |
| Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder. | Zillich E et al. | — | 2024 | → |
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