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Cannabinoids shift the basal ganglia microRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques

ABSTRACT: Epitranscriptomic modifications [N6-methyladenosine (m6A)] regulate various diseases, including cancer and inflammation. Despite their functional relevance in neural development and differentiation, the role of m6A modifications in HIV neuropathogenesis is unknown. Using anti-N6-methyladenosine (m6A) antibody-immunoprecipitation and microarray profiling, we identified m6A modifications in miRNAs in basal ganglia (BG) of uninfected (VEH) and SIV-infected Rhesus macaques (RMs) on combination anti-retroviral therapy (cART) and either VEH-treated (VEH/SIV/cART), or THC:CBD-treated (THC:CBD/SIV/cART). HIV/SIV infection promoted an overall hypomethylated miRNA m6A profile. While THC:CBD did not significantly impact the overall hypomethylated m6A profile, specific miRNAs predicted to target proinflammatory genes showed marked m6A hypomethylation compared to VEH-treated RMs. Additionally, specific BG m6A-modified miRNAs were detected in BG-derived extracellular vesicles. Mechanistically, the DRACH motif in the miR-194-5p seed region was significantly m6A hypomethylated in THC:CBD/SIV/cART RMs. Unlike wild-type, in-vitro transfected m6A-modified miR-194-5p mimics failed to downregulate STAT1 protein expression. Further, compared to VEH/SIV/cART RMs, THC:CBD significantly reduced m6A methylation of 44 miRNAs directly involved in regulating CNS network genes. Our findings indicate that m6A epitranscriptomic marks in the seed nucleotides can impair miRNA function and that cannabinoids may preserve it by reducing m6A methylation levels, thus, providing a mechanistic explanation underlying their anti-neuroinflammatory effects in HIV/SIV infection.

ORGANISM(S): Homo sapiens Macaca mulatta

PROVIDER: GSE296015 | GEO | 2025/06/15

REPOSITORIES: GEO

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Cannabinoids shift the basal ganglia microRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques

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