Dataset Information

The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus.

ABSTRACT: BACKGROUND:This study was aimed to explore the mRNA expression of m6A "writers" (METTL3, MTEEL14, and WTAP), "erasers" (FTO and ALKBH5), and "readers" (YTHDF2) in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients and investigate the relation between their expressions with clinical features. METHODS:In all, 54 SLE patients and 42 healthy controls (HC) were included in the current study. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to investigate the mRNA expression of m6A "writers," "erasers," and "readers" in PBMCs from SLE patients and HC. RESULTS:Decreased mRNA expression of MTEEL14, ALKBH5, and YTHDF2 was observed in SLE patients compared with those in HC (p < .001). The decreased mRNA expression of METTL14 was associated with white blood cell count (WBC) and monocyte count (M), this decreased mRNA expression of ALKBH5 was associated with C-reactive protein (CRP), neutrophil percentage (N%), lymphocyte percentage (L%), neutrophil-lymphocyte ratio (NLR), complement 3 (C3), and fever, and the decreased mRNA expression of YTHDF2 was associated with L%, NLR, C3, and fever. In addition, there was a positive correlation between mRNA expression of METTL14, ALKBH5, and YTHDF2 in PBMCs from SLE patients. Importantly, logistic regression analysis revealed that decreased mRNA expression of YTHDF2 was a risk factor for SLE. CONCLUSION:Taken all together, our findings suggested decreased YTHDF2 that was associated with disease activity may play an important role in the pathogenesis of SLE, METTL14 and ALKBH5 may be concomitantly decreased.

SUBMITTER: Luo Q

PROVIDER: S-EPMC7507441 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus.

Luo Qing Q Rao Jiayue J Zhang Lu L Fu Biqi B Guo Yang Y Huang Zikun Z Li Junming J

Molecular genetics & genomic medicine 20200625 9

<h4>Background</h4>This study was aimed to explore the mRNA expression of m6A "writers" (METTL3, MTEEL14, and WTAP), "erasers" (FTO and ALKBH5), and "readers" (YTHDF2) in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients and investigate the relation between their expressions with clinical features.<h4>Methods</h4>In all, 54 SLE patients and 42 healthy controls (HC) were included in the current study. Quantitative reverse transcription-polymerase chain re ...[more]

PMID: 32583611

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Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease with a complicated pathogenesis, and its aetiology has not been clearly unveiled. The lack of effective diagnosis and treatment methods makes it necessary to explore the molecular mechanism of SLE. We aimed to identify some critical signalling pathways and key competing endogenous RNAs (ceRNAs) underlying the molecular mechanism of SLE and to map out the systematic signalling networks by integrating the data on different kinds of RNAs.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from both SLE patients and healthy subjects, RNA was extracted from the PBMCs, and RNA libraries including ribosomal RNA-depleted strand-specific libraries and small RNA libraries were built for deep RNA sequencing (RNA-seq). RNA-seq yielded differential expression profiles of lncRNAs/circRNAs/miRNAs/mRNAs related to SLE. The DAVID database (v. 6.8) was employed for Gene Ontology (GO) and KEGG pathway analysis. ceRNA networks (circRNA/lncRNA-miRNA-mRNA) were constructed and visualized using Cytoscape software (v. 3.5.0). The TargetScan and miRanda databases were used to predict target relationships in ceRNA networks. qRT-PCR was used to verify our data.ResultsDifferential expression of ceRNAs related to SLE was detected in SLE patients' PBMCs: 644 mRNAs (384 upregulated, 260 downregulated), 326 miRNAs (223 upregulated, 103 downregulated), 221 lncRNAs (79 upregulated, 142 downregulated), and 31 circRNAs (21 upregulated, 10 downregulated). We drew ceRNA signalling networks made up of the differentially expressed mRNAs/miRNAs/lncRNAs/circRNAs mentioned above, and the hub genes included IRF5, IFNAR2, TLR7, IRAK4, STAT1, STAT2, C2, and Tyk2. These hub genes were involved in ceRNA signalling pathways, such as the IL-17 signalling pathway and type I interferon signalling pathway.ConclusionsWe explored the differential expression profiles of various kinds of ceRNAs and integrated signalling networks constructed by ceRNAs. Our findings offer new insights into the pathogenesis of SLE and hint at therapeutic strategies.

Project description:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by overactive inflammation and aberrant activation of lymphocytes. Chemokine C-X-C motif ligand 10 (CXCL10) has an important role in the initiation and deterioration of SLE. However, the expression levels of CXCL10 mRNA in T-helper (Th) cells and B lymphocytes from SLE patients have remained elusive. In the present study, a Bioinformatics analysis of differentially expressed gene (DEG) profiles obtained from RNA sequencing data for three matched samples was performed to explore the hub genes, mainly through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction analysis. Furthermore, the expression of CXCL10 in peripheral blood mononuclear cells (PBMCs), CD4+ Th cells and CD19+ B cells of 108 subjects, including 66 SLE patients and 42 healthy controls, was confirmed by reverse transcription-quantitative PCR. In addition, 4 single-nucleotide polymorphism (SNP) loci in the 3'-untranslated region of CXCL10 were assessed using the Snapshot SNP genotyping assay. A total of 152 clustered DEGs mainly accumulated in immune-associated GO terms and interferon-associated pathways were identified. The expression of CXCL10, one of the central genes in the interaction network cluster (the degree of interaction, MCODE score=28.414), was 6.27-fold higher in SLE patients compared with control patients. Furthermore, CXCL10 mRNA was confirmed to be elevated in PBMCs and CD19+ B cells of patients with SLE (P<0.001 for the two cell types). However, no significant difference in CD4+ T lymphocytes was present (P=0.881). In addition, no polymorphism was identified in four selected loci from the samples. Taken together, the present results demonstrated that CXCL10, one of the hub genes in the pathogenesis of SLE, is upregulated in PBMCs and B lymphocytes of patients with SLE, although none of the SNPs selected for analysis in the present study were identified to have any potential associations with SLE.

Project description:Background:Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression in the immune system, but their impact on neuropsychiatric systemic lupus erythematosus (NPSLE) remains unknown. Methods:RNA sequencing analysis was used to screen the comprehensive expression profile of lncRNAs and messenger RNAs (mRNAs) in peripheral blood mononuclear cells (PBMCs) from NPSLE patients, active SLE patients who had never experienced neuropsychiatric manifestations (Non-NPSLE) and healthy controls. Differentially expressed (DE) lncRNA levels were validated by qRT-PCR in 26 NPSLE patients, 31 Non-NPSLE patients and 30 healthy controls. Further, correlations of DE lncRNAs with clinical manifestations of NPSLE patients were analyzed. Finally, a bioinformatic analysis was performed to investigate the potential functions of DE genes. Results:Four hundred and fifty-one lncRNAs and 272 mRNAs were DE between the NPSLE patients and Non-NPSLE patients, among which, significantly upregulated expression levels of NONHSAT208182.1, NONHSAT182114.1, NONHSAT106801.2, NONHSAT039491.2, ENST00000356215, NONHSAT087499.2 and NONHSAT207026.1 while downregulated expression levels of NONHSAT001281.2 and NONHSAT024353.2 were further validated in PBMCs from NPSLE patients by qRT-PCR. Bioinformatic analysis suggested several gene ontology (GO) terms and signal pathways may play important roles in NPSLE development. Co-expression networks analysis indicated that 170 lncRNAs and 46 mRNAs were included in the co-expression network. The expression level of NONHSAT039491.2 was associated with the activity of SLE and the presence of anti-dsDNA, anti-RNP antibody, dizziness and headache. NONHSAT087499.2 level correlated with anti-RNA antibody, ENST00000356215 level correlated with olfactory threshold and oral ulcer. NONHSAT208182.1 level correlated with the presence of fever, unstable walking and urinary red blood cells. NONHSAT106801.2 correlated with frequency of B cells and the presence of fever. NONHSAT024353.2 level was associated with serum IgG levels and the presence of anti-SSA and disorder of consciousness. Conclusions:Our data provided comprehensive evidence regarding the differential expression of lncRNAs in PBMCs from NPSLE patients, indicating that these DE lncRNAs may play roles in NPSLE development. Our finding shed light on the understanding of the molecular mechanisms of lncRNAs in the pathogenesis of NPSLE.

Project description:Recent achievement in genetics and epigenetics has led to the exploration of the pathogenesis of systemic lupus erythematosus (SLE). Identification of differentially expressed genes and their regulatory mechanism(s) at whole-genome level will provide a comprehensive understanding of the development of SLE and its devastating complications, lupus nephritis (LN).We performed whole-genome transcription and DNA methylation analysis in PBMC of 30 SLE patients, including 15 with LN (SLE LN(+)) and 15 without LN (SLE LN(-)), and 25 normal controls (NC) using HumanHT-12 Beadchips and Illumina Human Methy450 chips. The serum proinflammatory cytokines were quantified using Bio-plex Human Cytokine 27-plex assay. Differentially expressed genes and differentially methylated CpG were analyzed with GenomeStudio, R, and SAM software. The association between DNA methylation and gene expression were tested. Gene interaction pathways of the differentially expressed genes were analyzed by IPA software.We identified 552 upregulated genes and 550 downregulated genes in PBMC of SLE. Integration of DNA methylation and gene expression profiling showed that 334 upregulated genes were hypomethylated, and 479 downregulated genes were hypermethylated. Pathway analysis on the differential genes in SLE revealed significant enrichment in interferon (IFN) signaling and toll-like receptor (TLR) signaling pathways. Nine IFN- and seven TLR-related genes were identified and displayed step-wise increase in SLE LN(-) and SLE LN(+). Hypomethylated CpG sites were detected on these genes. The gene expressions for MX1, GPR84, and E2F2 were increased in SLE LN(+) as compared to SLE LN(-) patients. The serum levels of inflammatory cytokines, including IL17A, IP-10, bFGF, TNF-?, IL-6, IL-15, GM-CSF, IL-1RA, IL-5, and IL-12p70, were significantly elevated in SLE compared with NC. The levels of IL-15 and IL1RA correlated with their mRNA expression. The upregulation of IL-15 may be regulated by hypomethylated CpG sites in the promotor region of the gene.Our study has demonstrated that significant number of differential genes in SLE were involved in IFN, TLR signaling pathways, and inflammatory cytokines. The enrichment of differential genes has been associated with aberrant DNA methylation, which may be relevant to the pathogenesis of SLE. Our observations have laid the groundwork for further diagnostic and mechanistic studies of SLE and LN.

Dataset Information

The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus.

Publications

The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus.

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