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Heterogeneous epigenetic variation converges on splicing dysregulation in opioid addiction

ABSTRACT: Disease heterogeneity presents a major challenge for genetic and epigenetic dissection of complex traits such as opioid use disorder (OUD). Here, we leverage individual heterogeneity to identify epigenetic variation linked to opioid overdose by profiling H3K27ac ChIP-seq in nucleus accumbens (NAc) from 91 overdose cases and accidental death controls. Machine learning models built on combinations of peaks distinguished cases from controls with high accuracy (AUROC = 0.95) and were enriched for OUD genetic risk. We defined individual-specific H3K27ac changes as Variant Enhancer Loci (VEL) and observed four-fold greater convergence on shared target genes in NAc than in prefrontal cortex. Convergent VEL target genes were enriched in independent OUD cohorts, and RNA splicing emerged as the top-enriched ontology. Knockdown of the splicing regulator CELF5 in iPSC-derived medium spiny neurons disrupted extracellular matrix organization genes. Collectively, this study provides new insights into opioid addiction and a conceptual framework for dissecting heterogeneous disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE341485 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:This dataset includes samples in the UTHealth Brain Collection (UTHBC) from Grimm et al 2022 "MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: further evidence for opioid-induced neurovascular alterations ", doi: 10.3389/fpsyt.2022.1025346. To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function. Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues. miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with potential functional impact on transcriptomic changes. Further, using correlation network analysis we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system and inflammatory pathways. These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs.

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Heterogeneous epigenetic variation converges on splicing dysregulation in opioid addiction

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