Deciphering HAND Pathogenesis Using Single-Nucleotide Omics Approaches
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ABSTRACT:
PROVIDER: PRJNA1261970 | ENA |
REPOSITORIES: ENA
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Project description:Although antiretroviral therapy (ART) effectively suppresses HIV-1 replication to undetectable levels and restores many immune parameters in people living with HIV (PLWH), these individuals remain at elevated risk for HIV-associated comorbidities. Among the most prevalent is neurocognitive impairment—a mild form of HIV-associated neurocognitive disorders (HAND)—which affects up to 50% of PLWH. Despite extensive investigation, the precise mechanisms underlying HAND pathogenesis remain unclear, in part due to its multifactorial nature. To address this, we conducted a comparative single-nucleus multi-omics analysis—integrating RNA sequencing (RNA-seq) and chromatin accessibility profiling (ATAC-seq)—of post-mortem brain tissues from HIV-infected individuals with and without HAND, as well as uninfected controls. Our results reveal substantial dysregulation in genes involved in inflammation, innate immunity, glycosylation, and cholesterol metabolism in HIV-infected brains (HAND+ and HAND−) relative to uninfected controls. Notably, these changes were further accentuated in HAND+ samples compared to HAND−, with microglia and oligodendrocytes emerging as the most affected cell populations—highlighting their potential central role in sustaining neuroinflammation. Interestingly, we observed a disconnect between transcriptomic and epigenomic signals: many inflammation-related genes located in accessible chromatin regions in HAND+ brains were not transcriptionally upregulated. This epigenetic priming—particularly in microglia and astrocytes—is consistent with the concept of trained immunity (TRIM), wherein prior exposures epigenetically “train” innate immune cells to respond differently to subsequent stimuli. Our findings suggest that maladaptive TRIM may be a key contributor to persistent neuroinflammation and the pathogenesis of HAND in the ART era.
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Project description:N6-methyladenosine (m6A) is the most abundant modification on mRNA, and is implicated in critical roles in development, physiology and disease. A major challenge in the field has been the inability to quantify m6A stoichiometry and the lack of antibody-independent methodologies for interrogating m6A. Here, we develop MASTER-seq for systematic quantitative profiling of m6A at single nucleotide resolution, building on differential cleavage by an RNAse at methylated sites. MASTER-seq permitted validation and de novo discovery of m6A sites, calibration of the performance of antibody based approaches, and quantitative tracking of m6A dynamics in yeast gametogenesis and mammalian differentiation. We discover that m6A stoichiometry is ‘hard-coded’ in cis via a simple and predictable code. This code accounts for ~50% of the variability in methylation levels and allows accurate prediction of m6A loss/acquisition events across evolution. MASTER-seq will allow quantitative investigation of m6A regulation in diverse cell types and disease states.
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