AI Article Synopsis

  • Structural and functional changes in the brain are linked to cocaine use disorder (CUD), with epigenetic and transcriptional alterations serving as potential molecular causes for these changes.
  • A study analyzing brain tissue from individuals with CUD identified significant differences in gene expression, particularly highlighting an upregulation of the gene ZFAND2A and changes in alternative splicing that affect neuron pathways.
  • The findings suggest important biological processes like synaptic signaling and neuron morphogenesis are disrupted in CUD, and propose that drugs targeting glucocorticoid receptors could help reverse these expression changes.

Article Abstract

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464785PMC
http://dx.doi.org/10.1038/s41398-024-03139-9DOI Listing

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