Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry

Huggett, Spencer B.; Ikeda, Ami S.; McGeary, John E.; Kaun, Karla R.; Palmer, Rohan

doi:10.3390/genes13061045

Cited by 7 publications

(7 citation statements)

References 45 publications

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“…A study evaluating mRNA alternative splicing in the human postmortem dlPFC, NAc, and midbrain associated with OUD identified eight differential spliced genes in morphine addiction ( 64 ), one of which was identified in our analysis: GABBR1 . In addition, they observed five spliced genes in the dlPFC, NAc, and ventral midbrain ( 64 ), including two genes with differential mCpHs found in our work: HERC1 and BIN1 . These results support an important gene regulatory role of OUD-linked differential mCpHs.…”

Section: Discussionmentioning

confidence: 91%

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Nagamatsu

Rompala²,

Hurd³

et al. 2023

Front. Psychiatry

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IntroductionDNA methylation (DNAm), an epigenetic mechanism, has been associated with opioid use disorder (OUD) in preclinical and human studies. However, most of the studies have focused on DNAm at CpG sites. DNAm at non-CpG sites (mCpHs, where H indicates A, T, or C) has been recently shown to have a role in gene regulation and to be highly abundant in neurons. However, its role in OUD is unknown. This work aims to evaluate mCpHs in the human postmortem orbital frontal cortex (OFC) in the context of OUD.MethodsA total of 38 Postmortem OFC samples were obtained from the VA Brain Bank (OUD = 12; Control = 26). mCpHs were assessed using reduced representation oxidative bisulfite sequencing in neuronal nuclei. Differential analysis was performed using the “methylkit” R package. Age, ancestry, postmortem interval, PTSD, and smoking status were included as covariates. Significant mCpHs were set at q-value < 0.05. Gene Ontology (GO) and KEGG enrichment analyses were performed for the annotated genes of all differential mCpH loci using String, ShinyGO, and amiGO software. Further, all annotated genes were analyzed using the Drug gene interaction database (DGIdb).ResultsA total of 2,352 differentially methylated genome-wide significant mCpHs were identified in OUD, mapping to 2,081 genes. GO analysis of genes with differential mCpH loci showed enrichment for nervous system development (p-value = 2.32E-19). KEGG enrichment analysis identified axon guidance and glutamatergic synapse (FDR 9E-4–2.1E-2). Drug interaction analysis found 3,420 interactions between the annotated genes and drugs, identifying interactions with 15 opioid-related drugs, including lofexidine and tizanidine, both previously used for the treatment of OUD-related symptoms.ConclusionOur findings suggest a role of mCpHs for OUD in cortical neurons and reveal important biological pathways and drug targets associated with the disorder.

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Section: Discussionmentioning

confidence: 91%

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Nagamatsu

Rompala²,

Hurd³

et al. 2023

Front. Psychiatry

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“…Interestingly, among our top findings, we found Bridging Integrator 1 ( BIN1 ) for which differential alternative splicing in the brain has been described in OUD. BIN1 was the only differential AS gene in OUD that was conserved across all investigated brain regions; dlPFC, NAc, and midbrain 26 . Further, AS events in Bin1 were identified in the mouse brain in a study on splicing alterations associated with cocaine self-administration 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have identified differential alternative splicing in alcohol use disorder 25 and opioid use disorder (OUD) 26 in the human brain, however, RNA splicing alterations have not been characterized in human CUD so far. In the differential alternative splicing analysis, we found N=98 statistically significant genes containing AS intron clusters.…”

Section: Discussionmentioning

confidence: 99%

“…The differential intron excision analysis results in an estimate for the change in the percent spliced in measure (ΔPSI) for each intron in a cluster and an FDR-adjusted p-value for the cluster in which the differential splicing events were detected. Differential splicing events in clusters with |dPSI| > 0.025 and an FDR-adjusted q-value<0.05 were considered statistically significant 26 . Visualizations for the differentially spliced clusters and genes were created using the leafviz extension in leafCutter.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to epigenetics and transcription, alterations of alternative splicing might contribute to the neurobiological changes in the CUD brain, as shown in other SUDs. Previous studies using postmortem human brain tissue from individuals with alcohol use disorder (AUD) [23][24][25] and opioid use disorder (OUD) 26 detected differential alternative splicing in transcripts of genes implicated in neuropsychiatric disorders, such as BIN1, FLOT1, and ELOVL7 suggesting RNA splicing alterations to be a further molecular mechanism in the neurobiology of SUDs. While a recent study using a cocaine self-administration model in mice showed widespread changes in alternative splicing in multiple brain regions 27 , no systematic evaluation of splicing alterations in human CUD was performed so far.…”

Section: Introductionmentioning

confidence: 99%

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Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

Zillich,

Belschner,

Avetyan

et al. 2024

Preprint

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Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N=42) and transcriptomic (N=25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N=1,057 differentially expressed genes (p<0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q<0.05). Differential alternative splicing (AS) analysis revealed N=98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.

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It is not just about transcription: involvement of brain RNA splicing in substance use disorders

Carvalho,

Lasek

2024

J Neural Transm

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Alternative splicing is a co-transcriptional process that significantly contributes to the molecular landscape of the cell. It plays a multifaceted role in shaping gene transcription, protein diversity, and functional adaptability in response to environmental cues. Recent studies demonstrate that drugs of abuse have a profound impact on alternative splicing patterns within different brain regions. Drugs like alcohol and cocaine modify the expression of genes responsible for encoding splicing factors, thereby influencing alternative splicing of crucial genes involved in neurotransmission, neurogenesis, and neuroinflammation. Notable examples of these alterations include alcohol-induced changes in splicing factors such as HSPA6 and PCBP1, as well as cocaine's impact on PTBP1 and SRSF11. Beyond the immediate effects of drug exposure, recent research has shed light on the role of alternative splicing in contributing to the risk of substance use disorders (SUDs). This is exemplified by exon skipping events in key genes like ELOVL7, which can elevate the risk of alcohol use disorder. Lastly, drugs of abuse can induce splicing alterations through epigenetic modifications. For example, cocaine exposure leads to alterations in levels of trimethylated lysine 36 of histone H3, which exhibits a robust association with alternative splicing and serves as a reliable predictor for exon exclusion. In summary, alternative splicing has emerged as a critical player in the complex interplay between drugs of abuse and the brain, offering insights into the molecular underpinnings of SUDs.

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Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry

Cited by 7 publications

References 45 publications

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

It is not just about transcription: involvement of brain RNA splicing in substance use disorders

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