Immunological profile of lactylation-related genes in Crohn’s disease: a comprehensive analysis based on bulk and single-cell RNA sequencing data
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ABSTRACT:
SUBMITTER: Wu J
PROVIDER: S-EPMC10960451 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Glycolysis-related lactylation has gained wide attention for regulating various cellular functions and diseases. Nevertheless, its intricate involvement in intervertebral disc degeneration (IVDD) is not yet fully understood. In this study, we unrevealed the intricate association between elevated lactylation levels and the development of IVDD. Subsequently, we harvested the lactylation-related genes (LRGs) and systematically analysed the expression levels of these genes to establish a gene signature related to IVDD through multiple bulk RNA sequencing data. Six hub LRGs were determined and closely associated with the increased severity of IVDD. Among the six genes, CBX3 was the most upregulated in both in vivo and in vitro experiments. Furthermore, molecular docking identified atosiban acetate as a specific inhibitor for CBX3, and inhibiting the expression of CBX3 using atosiban acetate significantly repressed the glycolysis activity and global lactylation level, thus alleviating the progression of IVDD. In conclusion, the lactylation correlates positively with IVDD and the LRG signature could be used as a biomarker for the effective clinical treatment of IVDD. CBX3 emerged as one of the key LRGs in IVDD, and atosiban acetate, as a specific inhibitor for CBX3, may be a promising therapeutic candidate for IVDD by affecting lactylation.
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Project description:Background and objectivesSpinal cord injury (SCI) results in significant neurological deficits, and microglia play the critical role in regulating the immune microenvironment and neurological recovery. Protein lactylation has been found to modulate the function of immune cells. Therefore, this study aimed to elucidate the effects of glycolysis-derived lactate on microglial function and its potential neuroprotective mechanisms via lactylation after SCI.MethodsSingle-cell RNA sequencing (scRNA-seq) data were obtained from figshare to analyze cellular and molecular alterations within the spinal cord post-SCI, further focusing on the expression of microglia-related genes for cell sub-clustering, trajectory analysis, and glycolysis function analysis. We also evaluated the expression of lactylation-related genes in microglia between day 7 after SCI and sham group. Additionally, we established the mice SCI model and performed the bulk RNA sequencing in a time-dependent manner. The expression of glycolysis- and lactylation-related genes was evaluated, as well as the immune infiltration analysis based on the lactylation-related genes. Then, we investigated the bio-effects of lactate on the inflammation and polarization phenotype of microglia. Finally, adult male C57BL/6 mice were subjected to exercise first to increase lactate level, before SCI surgery, aiming to evaluate the protective effects of lactate-mediated lactylation of microglia-related proteins on SCI.ResultsscRNA-seq identified a subcluster of microglia, recombinant chemokine C-X3-C-motif receptor 1+ (CX3CR1+) microglia, which is featured by M1-like phenotype and increased after SCI. KEGG analysis revealed the dysfunctional glycolysis in microglia after SCI surgery, and AUCell analysis suggested that the decreased glycolysis an increased oxidative phosphorylation in CX3CR1+ microglia. Differential gene analysis suggested that several lactylation-related genes (Fabp5, Lgals1, Vim, and Nefl) were downregulated in CX3CR1+ microglia at day 7 after SCI, further validated by the results from bulk RNA sequencing. Immunofluorescence staining indicated the expression of lactate dehydrogenase A (LDHA) in CX3CR1+ microglia also decreased at day 7 after SCI. Cellular experiments demonstrated that the administration of lactate could increase the lactylation level and inhibit the pro-inflammatory phenotype in microglia. Functionally, exercise-mediated lactate production resulted in improved locomotor recovery and decreased inflammatory markers in SCI mice compared to SCI alone.ConclusionsIn the subacute phase of SCI, metabolic remodeling in microglia may be key therapeutic targets to promote nerve regeneration, and lactate contributed to neuroprotection after SCI by influencing microglial lactylation and inflammatory phenotype, which offered a novel approach for therapeutic intervention.
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Project description:Hepatocellular carcinoma (HCC) poses a continual therapeutic challenge owing to its elevated incidence and unfavourable prognosis, underscoring the critical need for the discovery of new molecular targets for detection and therapy. This work included the analysis of three publically accessible HCC datasets from TCGA and GEO. Instrumental variables (IVs) were derived via expression quantitative trait loci (eQTL) analysis, then followed by two-sample Mendelian randomisation (MR) analysis utilising publically available summary statistics. Key disease-associated genes were identified by assessing odds ratios and connecting them with differentially expressed genes across the datasets. The potential molecular mechanisms of these genes were clarified by functional enrichment analysis, clinical data analysis, single-cell RNA sequencing, GSEA, immune cell infiltration, and immune checkpoint analysis. These findings were then confirmed by Western blotting, immunohistochemistry, and quantitative PCR. By synthesising the outcomes from differential analysis of the databases, we found two genes, SERPING1 and STEAP3, that may be crucial in the beginning and development of HCC. These genes have a role in vital biological pathways and functions, such as metabolic regulation and macrophage activation. The significance of immunological-mediated processes in HCC was further highlighted by CIBERSORT analysis, which revealed a specific pattern of immune cell infiltration and the location of immunological checkpoints in the illness. The findings elucidate the molecular mechanisms of HCC and underscore critical genes implicated in its pathogenesis. SERPING1 and STEAP3 affect tumour cells and modify the tumour microenvironment (TME), indicating that targeting these genes may offer a viable immunotherapeutic approach for HCC in clinical settings.
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Project description:Background: Sepsis is a pathological state resulting from dysregulated immune response in host during severe infection, leading to persistent organ dysfunction and ultimately death. Senescence-associated genes (SAGs) have manifested their potential in controlling the proliferation and dissemination of a variety of diseases. Nevertheless, the correlation between sepsis and SAGs remains obscure and requires further investigation. Methods: Two RNA expression datasets (GSE28750 and GSE57065) specifically related to sepsis were employed to filter hub SAGs, based on which a diagnostic model predictive of the incidence of sepsis was developed. The association between the expression of the SAGs identified and immune-related modules was analyzed employing Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Microenvironment Cell Populations-counter (MCP-counter) analysis. The identified genes in each cohort were clustered by unsupervised agreement clustering analysis and weighted gene correlation network analysis (WGCNA). Results: A diagnostic model for sepsis established based on hub genes (IGFBP7, GMFG, IL10, IL18, ETS2, HGF, CD55, and MMP9) exhibited a strong clinical reliability (AUC = 0.989). Sepsis patients were randomly assigned and classified by WGCNA into two clusters with distinct immune statuses. Analysis on the single-cell RNA sequencing (scRNA-seq) data revealed high scores of SAGs in the natural killer (NK) cells of the sepsis cohort than the healthy cohort. Conclusion: These findings suggested a close association between SAGs and sepsis alterations. The identified hub genes had potential to serve as a viable diagnostic marker for sepsis.
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