Commentary: Long Non-Coding RNA Gene Polymorphisms and Their Expression Levels in Patients With Rheumatoid Arthritis.
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ABSTRACT:
SUBMITTER: Hernandez-Bello J
PROVIDER: S-EPMC8695717 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Long non-coding RNAs (lncRNAs) are increasingly recognized to play important roles in multiple autoimmune diseases. This study aimed to evaluate the association of four lncRNAs (ANRIL, lnc-DC, MALAT1, ZFAS1) genes single nucleotide polymorphisms (SNPs) with susceptibility to rheumatoid arthritis (RA) patients, as well as their expression levels. Seventeen SNPs of the four lncRNAs were genotyped in a cohort of 660 RA patients and 710 controls using improved multiple ligase detection reaction (iMLDR). The lncRNAs expressions in peripheral blood mononuclear cells (PBMCs) from 120 RA patients and 120 controls were detected by qRT-PCR. No significant differences were found for the allele and genotype frequencies distribution of ANRIL SNPs (rs1412830, rs944796, rs61271866, rs2518723, rs3217992), lnc-DC SNPs (rs7217280, rs10515177), MALAT1 SNPs (rs619586, rs4102217, rs591291, rs11227209, rs35138901), ZFAS1 SNPs (rs237742, rs73116127, rs6125607, rs6125608) between RA patients and normal controls (all P > 0.05). The genotype effects of dominant and recessive models were also evaluated, but no significant association was found. In addition, our results demonstrated that the rs944796 G allele, rs2518723 T allele, rs3217992 T allele frequencies were significantly associated with anti-CCP in RA patients (all P < 0.05). The haplotype CGTA frequency for ZFAS1 was significantly higher in RA patients (P = 0.036). Compared with normal controls, the expression levels of ANRIL, lnc-DC, MALAT1, ZFAS1 in PBMCs were significantly reduced in RA patients (all P < 0.001). Moreover, ZFAS1 expression was negatively associated with CRP in RA patients (P = 0.002). In summary, ANRIL, lnc-DC, MALAT1, and ZFAS1 genes SNPs were not associated with RA susceptibility, while altered ANRIL, lnc-DC, MALAT1, ZFAS1 levels in RA patients suggested that these lncRNAs might play a role in RA.
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Project description:This study aimed to explore the effects of long non-coding RNA (lncRNA) expression on rheumatoid arthritis (RA). LncRNA expression profiles were obtained from the synovial tissues of five RA patients and five age-/gender-matched controls by RNA-Seq. Six candidate lncRNAs were then chosen and their levels in synovial fluid further examined in 25 RA patients and 25 health controls using RT-qPCR. The effects of lncRNA RP11-83J16.1 overexpression and knockdown on RA fibroblast-like synoviocytes (RA-FLS) function, inflammation state, and URI1, FRAT1, and β-catenin levels were assessed. After RNA-Seq, lncRNA expression profiles clearly distinguished RA patients from controls, and 190 upregulated lncRNAs and 131 downregulated lncRNAs were identified, which were mainly enriched in proliferative/immune/inflammatory pathways. Results of RT-qPCR showed that the levels of lncRNAs MTCO2P12, KCNQ5-IT1 and RP11-83J16.1 were increased, whereas lncRNAs LINC00570, RP11-342M1.6, and REXO1L4P were decreased in RA patients compared to controls. Notably, lncRNA RP11-83J16.1 correlated with increased inflammation and disease activity in RA patients. Additionally, lncRNA RP11-83J16.1 promoted cell proliferation, migration, invasion and inflammation, reduced apoptosis, and positively regulates cellular URI1, FRAT1 and β-catenin expression in RA-FLS. Rescue experiments revealed that URI1 overexpression compensated for the regulatory effects of lncRNA RP11-83J16.1 knockdown in RA-FLS. In conclusion, lncRNA RP11-83J16.1, a novel lncRNA identified by RNA-Seq, correlates with increased risk and disease activity of RA, and promotes RA-FLS proliferation, migration, invasion and inflammation by regulating URI1 and downstream β-catenin pathway components.
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Project description:Whilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.
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Project description:Accumulating evidence suggests long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Here, we aimed to define the role of HOXA transcript at the distal tip (HOTTIP) in RA pathogenesis in relation to SFRP1 methylation and Wnt signaling pathway. HOTTIP was found highly expressed, and SFRP1 was hypermethylated in RA synovial fibroblasts (RASFs). Next, gain- or loss-of-function experiments were conducted in RASFs to explore the effects of HOTTIP on the biological behaviors of RASFs. Silencing of HOTTIP or overexpression of SFRP1 inhibited RASF proliferation, invasion, and migration, while enhancing apoptosis. The relationship among HOTTIP, SFRP1, and Dnmt3b was determined using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays. The regulatory mechanisms of HOTTIP/Dnmt3b/SFRP1 were explored by altering their expression in RASFs. It was noted that HOTTIP could induce SFRP1 promoter methylation through recruitment of Dnmt3b and activate the Wnt signaling pathway. Finally, a rat RA model was established in order to evaluate the in vivo effects of HOTTIP and SFRP1, which suggested that HOTTIP silencing or SFRP1 elevation inhibited the progression of RA in vivo. Our key findings demonstrate the anti-inflammatory ability of HOTTIP silencing in RA through SFRP1 promoter demethylation. These findings support HOTTIP as a candidate anti-arthritis target.
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Project description:Long non-coding RNA (lncRNA) plays a contributory role in rheumatoid arthritis (RA). In this review, we summarized the current findings of lncRNAs in RA, including cellular function and the potential mechanisms. Serum lncRNA levels are associated with serum proinflammatory cytokines and disease activity. LncRNAs regulate proliferation, migration, invasion and apoptosis of RA fibroblast-like synoviocytes (FLSs), modulate the differentiation of T lymphocytes and macrophages, and affect bone formation-destruction balance of chondrocytes. Besides, lncRNAs are involved in inflammation and cell motivation signaling pathways. In-depth research on lncRNAs may help elucidate the pathogenesis of RA and provides clues for novel treatment targets.
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Project description:Long non-coding RNAs (lncRNAs) and their target microRNAs were documented in multiple studies to have a significant role in different joint disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA). The current work aimed to determine the potential role of lnc-PVT1 and miR-146a as promising biomarkers to distinguish between RA, OA patients, and healthy individuals. The expression levels of lnc-PVT1 and its target miR-146a in the serum were measured for three different groups, including patients with RA (40), OA patients (40), and healthy controls (HCs) (40). Participating individuals were subjected to a full history investigation and clinical examination. Blood samples were tested for ESR, RF, CBC, as well as liver and renal functions. Serum was used to detect the relative expression levels of lnc-PVT1 and miR-146a and we correlated the levels with RA and OA activity and severity signs. Lnc-PVT1 expression level was greater among patients with RA compared to that of OA patients, with a fold change median of 2.62 and 0.22, respectively (p = 0.001). The miR-146a fold change was significantly demonstrated between the RA, OA, and HCs groups. There was no correlation between both biomarkers with the disease activity scales (DAS28) of RA, the Knee injury Osteoarthritis Outcome Score (KOOS), or any sign of detection of the disease severity of OA. lnc-PVT1 and miR-146a could be considered as promising biomarkers for the diagnosis of RA and OA and may have an important role as therapeutic targets in the future.
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Project description:The human transcriptome is primarily composed of long non-coding RNAs (lncRNAs), which are key regulatory molecules of multiple biological processes. In the present study, the expression profiles of lncRNAs in the peripheral blood and CD4+ T cells of patients with active rheumatoid arthritis (RA) were determined. Based on the expression profiles, 493 lncRNAs and 374 mRNAs were identified to be differentially expressed in the peripheral blood of active RA patients and healthy donors. Further verification of lncRNAs was performed using reverse transcription-quantitative (RT-q) PCR analysis of peripheral blood from 5 healthy donors and 5 patients with active RA and 14 additional differentially expressed genes were identified. CD4+ T cells in peripheral blood from 12 patients with active RA and 8 healthy donors were isolated using magnetic beads and qPCR was used to assess differentially expressed lncRNAs. The results suggested that 7 lncRNAs were upregulated and 2 were downregulated. The results indicated that these 9 lncRNAs may be involved in the pathogenesis of RA. An increased ratio of Th17: T-regulatory (Treg) cells was also observed. It may be hypothesized that LncRNAs serve important roles in the differentiation of CD4+ T cells. Receiver operating characteristic curve analysis suggested that these 9 lncRNAs are of potential clinical diagnostic value for RA. Pearson correlation analysis indicated that the correlation coefficient between Ensembl transcript (ENST)00000569543 and complement C4 was 0.623 (P<0.05), and that between ENST00000420096 and anti-cyclic citrullinated peptide antibody or disease activity evaluation score, the correlation coefficient was 0.662 and 0.605, respectively (P<0.05 for each). In conclusion, the results of the present study suggest a possible role of lncRNAs in the differentiation of CD4+ T cells and the pathogenesis of RA, as well as the potential value as diagnostic biomarkers for active RA.
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