Dataset Information

Integrative Analysis of m⁶A Regulator-Mediated RNA Methylation Modification Patterns and Immune Characteristics in Lupus Nephritis.

ABSTRACT:

Background

There is growing evidence to demonstrate that the epigenetic regulation of immune characteristics, especially for N6-methyladenosine (m⁶A) RNA methylation. However, how m⁶A methylation is involved in lupus nephritis (LN) is still unclear. This study aimed to determine the role of m⁶A RNA methylation and their association with the immune microenvironment in LN.

Methods

In total, 87 glomeruli (73 LN, 14 living healthy donors), 110 tubulointerstitium (95 LN, 15 living healthy donors), and 21 kidney whole tissue samples (14 LN, 7 controls) were included in our research to evaluate the expression levels of m⁶A regulators. CIBERSORT was used to assess the abundance of infiltrating immunocytes. The m⁶A regulator gene signature for LN was identified using LASSO-logistic regression and verified with external data. Consensus clustering algorithms were used for the unsupervised cluster analysis of m⁶A modification patterns in LN. Single-sample gene-set enrichment analysis and gene set variation analysis algorithms were employed to assess the activity of immune responses and other functional pathways. Weighted gene co-expression network analysis and protein-protein interaction networks were used to identify m⁶A methylation markers. Lastly, the Nephroseq V5 tool was used to analyze the correlation between m⁶A markers and renal function.

Results

We found that the expression of m⁶A regulators was more significantly different in the glomeruli in LN compared with tubulointerstitium and whole kidney tissue. We established an m⁶A regulator signature, comprised of METTL3, WTAP, YTHDC2, YTHDF1, FMR1, and FTO, that can easily distinguish LN and healthy individuals. Two distinct m⁶A modification patterns based on 18 m⁶A regulators were determined, with significant differences in m⁶A regulator expression, immune microenvironment, biological functional pathways, and clinical characteristics. Activated NK cells, most immune responses, and HLA genes had strong correlations with m⁶A regulators. Seven m⁶A markers were identified and demonstrated a meaningful correlation with GFR, indicating that they are potential prognostic biomarkers.

Conclusion

This study emphasized that m⁶A RNA methylation and the immune microenvironment are closely linked in LN. A better understanding of m⁶A modification patterns provide a basis for the development of novel therapeutic options for LN.

SUBMITTER: Zhao H

PROVIDER: S-EPMC8454410 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The epigenetic modifier N6-methyladenosine (m6A), recognized as the most prevalent internal modification in messenger RNA (mRNA), has recently emerged as a pivotal player in immune regulation. Its dysregulation has been implicated in the pathogenesis of various autoimmune conditions. However, the implications of m6A modification within the immune microenvironment of Sjögren's syndrome (SS), a chronic autoimmune disorder characterized by exocrine gland dysfunction, remain unexplored. Herein, we leverage an integrative analysis combining public database resources and novel sequencing data to investigate the expression profiles of m6A regulatory genes in SS. Our cohort comprised 220 patients diagnosed with SS and 62 healthy individuals, enabling a comprehensive evaluation of peripheral blood at the transcriptomic level. We report a significant association between SS and altered expression of key m6A regulators, with these changes closely tied to the activation of CD4+ T cells. Employing a random forest (RF) algorithm, we identified crucial genes contributing to the disease phenotype, which facilitated the development of a robust diagnostic model via multivariate logistic regression analysis. Further, unsupervised clustering revealed two distinct m6A modification patterns, which were significantly associated with variations in immunocyte infiltration, immune response activity, and biological function enrichment in SS. Subsequently, we proceeded with a screening process aimed at identifying genes that were differentially expressed (DEGs) between the two groups distinguished by m6A modification. Leveraging these DEGs, we employed weight gene co-expression network analysis (WGCNA) to uncover sets of genes that exhibited strong co-variance and hub genes that were closely linked to m6A modification. Through rigorous analysis, we identified three critical m6A regulators - METTL3, ALKBH5, and YTHDF1 - alongside two m6A-related hub genes, COMMD8 and SRP9. These elements collectively underscore a complex but discernible pattern of m6A modification that appears to be integrally linked with SS's pathogenesis. Our findings not only illuminate the significant correlation between m6A modification and the immune microenvironment in SS but also lay the groundwork for a deeper understanding of m6A regulatory mechanisms. More importantly, the identification of these key regulators and hub genes opens new avenues for the diagnosis and treatment of SS, presenting potential targets for therapeutic intervention.

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Project description:Background: 5-Methylcytosine (m5C) plays essential roles in hepatocellular carcinoma (HCC), but the association between m5C regulation and immune cell infiltration in HCC has not yet been clarified. Methods: In this study, we analysed 371 patients with HCC from The Cancer Genome Atlas (TCGA) database, and the expression of 13 m5C regulators was investigated. Additionally, gene set variation analysis (GSVA), unsupervised clustering analysis, single-sample gene set enrichment analysis (ssGSEA), correlation analysis, and immunohistochemical (IHC) staining were performed. Results: Among the 371 patients, 41 had mutations in m5C regulators, the frequency of which was 11.26%. Compared with normal hepatic tissues, the expression of m5C regulators with copy number variations (CNVs) expansion was significantly higher than that in HCC tissues. Then, we identified three m5C modification patterns that had obvious tumour microenvironment (TME) cell infiltration characteristics. The prognostic analysis of the three major m5C modification subtypes showed that Cluster-2 had a clear survival advantage over the others. In addition, we found that DNMT1 was highly expressed in tumour tissues compared with normal tissues in a tissue microarray (TMA) and that it was positively correlated with many TME-infiltrating immune cells. High expression of the m5C regulator DNMT1 was related to a poor prognosis in patients with HCC. Furthermore, we developed three distinct Immu-clusters. Importantly, mRNAs related to the transcription of growth factor β (TGF-β)/EMT pathway were significantly up-regulated in Immu-cluster 2, indicating that this cluster is considered to be the immune rejection phenotype. Immu-cluster 3 showed elevated expression of mRNAs related to immune checkpoint genes. Conclusion: Our work revealed the association between m5C modification and immune regulators in the TME. These findings also suggest that DNMT1 has great potential as a prognostic biomarker and therapeutic target for HCC.

Dataset Information

Integrative Analysis of m⁶A Regulator-Mediated RNA Methylation Modification Patterns and Immune Characteristics in Lupus Nephritis.

Background

Methods

Results

Conclusion

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Tweets

Dataset Information

Integrative Analysis of m6A Regulator-Mediated RNA Methylation Modification Patterns and Immune Characteristics in Lupus Nephritis.

Background

Methods

Results

Conclusion

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Integrative Analysis of m⁶A Regulator-Mediated RNA Methylation Modification Patterns and Immune Characteristics in Lupus Nephritis.