Integrated analysis of single-cell RNA-seq and bulk RNA-seq reveals RNA N6-methyladenosine modification associated with prognosis and drug resistance in acute myeloid leukemia
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC10644381 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:N6-Methyladenosine-related long noncoding RNAs play an essential role in many cancers' development. However, the relationship between m6A-related lncRNAs and acute myelogenous leukemia (AML) prognosis remains unclear. We systematically analyzed the association of m6A-related lncRNAs with the prognosis and tumor immune microenvironment (TME) features using the therapeutically applicable research to generate effective treatment (TARGET) database. We screened 315 lncRNAs associated with AML prognosis and identified nine key lncRNAs associated with m6A by the LASSO Cox analysis. A model was established based on these nine lncRNAs and the predictive power was explored in The Cancer Genome Atlas (TCGA) database. The areas under the ROC curve of TARGET and TCGA databases for ROC at 1, 3, and 5 years are 0.701, 0.704, and 0.696, and 0.587, 0.639, and 0.685, respectively. The nomogram and decision curve analysis (DCA) showed that the risk score was more accurate than other clinical indicators in evaluating patients' prognoses. The clusters with a better prognosis enrich the AML pathways and immune-related pathways. We also found a close correlation between prognostic m6A-related lncRNAs and tumor immune cell infiltration. LAG3 expression at the immune checkpoint was lower in the worse prognostic cluster. In conclusion, m6A-related lncRNAs partly affected AML prognosis by remodeling the TME and affecting the anticarcinogenic ability of immune checkpoints, especially LAG3 inhibitors. The prognostic model constructed with nine key m6A-related lncRNAs can provide a method to assess the prognosis of AML patients in both adults and children.
| S-EPMC9115802 | biostudies-literature
Project description:Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (m6A) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and m6A modification abrogates immune gene activation and adjuvant activity. m6A reader YTHDF2 sequesters m6A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m6A-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.
| S-EPMC6778039 | biostudies-literature
Project description:BackgroundThe association between acute myeloid leukemia (AML) and macrophage remains to be deeply explored.MethodsGene expression profiles and clinical variable characteristics of AML patients were collected from TCGA, GEO, and TARGET databases. Consensus clustering was employed to construct the macrophage-related clusters. The macrophage-related index (MRI) was constructed using the LASSO and multivariate Cox analysis. The GSE71014 and TARGET datasets were utilized as external validation sets. Single-cell sequencing data for AML (GSE116256) was adopted to analyze modeled gene expression levels in cells.ResultsTwo macrophage-related clusters with different prognostic and immune infiltration characteristics were constructed in AML. Cluster B had a poorer prognosis, more cancer-promoting pathway enrichment, and an immunosuppressive microenvironment. Relied on the MRI, patients of different groups showed different levels of immune infiltration, different mutations, and prognoses. LGALS1 and BCL2A1 may play roles in promoting cancer in AML, while ELANE may have a significant effect on suppressing cancer.ConclusionMacrophage-related genes (MRGs) had significant impacts on the occurrence and progression of AML. MRI may better evaluate the prognosis and immune features of AML patients.
| S-EPMC10776189 | biostudies-literature
Project description:Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The discovery of N6-methyladenosine (m6A), a predominantly internal epigenetic modification in eukaryotes mRNA, heralded the creation of the field of epi-transcriptomics. This post-transcriptional RNA modification is dynamic and reversible, and is regulated by methylases, demethylases and proteins that preferentially recognize m6A modifications. Altered m6A levels affect RNA processing, degradation and translation, thereby disrupting gene expression and key cellular processes, ultimately resulting in tumor initiation and progression. Furthermore, inhibitors and regulators of m6A-related factors have been explored as therapeutic approaches for treating cancer. In the present review, the mechanisms of m6A RNA modification, the clinicopathological relevance of m6A alterations, the type and frequency of alterations and the multiple functions it regulates in different types of cancer are discussed.
| S-EPMC7278081 | biostudies-literature
Project description:The methylation of N6-methyladenosine (m6A) involves writers, erasers, and readers, acting synergistically in posttranscriptional regulation. These processes influence various biological processes, including plant floral transition. However, the specific role of m6A modifications in photoperiod sensitivity in cotton (Gossypium hirsutum) remains obscure. To elucidate this, in this study, we conducted transcriptome-wide m6A sequencing during critical flowering transition stages in the photoperiod-sensitive wild G. hirsutum var. yucatanense (yucatanense) and the photoperiod-insensitive cultivated cotton G. hirsutum acc. TM-1 (TM-1). Our results revealed significant variations in m6A methylation of 2 cotton varieties, with yucatanense exhibiting elevated m6A modification levels compared with TM-1 under long-day conditions. Notably, distinct m6A peaks between TM-1 and yucatanense correlated significantly with photoperiod sensitivity. Moreover, our study highlighted the role of the demethylase G. hirsutum ALKB homolog 5 (GhALKBH5) in modulating m6A modification levels. Silencing GhALKBH5 led to a decreased mRNA level of key photoperiodic flowering genes (GhADO3, GhAGL24, and GhFT1), resulting in delayed bud emergence and flowering. Reverse transcription quantitative PCR analyses confirmed that silencing GhADO3 and GhAGL24 significantly downregulated the expression of the floral integrator GhFT1. Collectively, our findings unveiled a transcriptional regulatory mechanism in which GhALKBH5-mediated m6A demethylation of crucial photoperiodic flowering transcripts modulated photoperiod sensitivity in cotton.
| S-EPMC11444288 | biostudies-literature
Project description:Molecular manipulation of susceptibility (S) genes that are antipodes to resistance (R) genes has been adopted as an alternative strategy for controlling crop diseases. Here, we show the S gene encoding Triticum aestivum m6A methyltransferase B (TaMTB) is identified by a genome-wide association study and subsequently shown to be a positive regulator for wheat yellow mosaic virus (WYMV) infection. TaMTB is localized in the nucleus, is translocated into the cytoplasmic aggregates by binding to WYMV NIb to upregulate the m6A level of WYMV RNA1 and stabilize the viral RNA, thus promoting viral infection. A natural mutant allele TaMTB-SNP176C is found to confer an enhanced susceptibility to WYMV infection through genetic variation analysis on 243 wheat varieties. Our discovery highlights this allele can be a useful target for the molecular wheat breeding in the future.
| S-EPMC9629889 | biostudies-literature
Project description:BackgroundN6-methyladenosine (m6A) methylation epigenetically regulates normal hematopoiesis and plays a role in the pathogenesis of acute myeloid leukemia (AML). However, its potential value for prognosis remains elusive.MethodsAnalysis of the datasets downloaded from The Cancer Genome Atlas and Genotype Tissue Expression databases revealed that the expression level of 20 regulators related to m6A RNA methylation differ between patients with AML and normal individuals. A prognostic risk model with three genes (YTHDF3, IGF2BP3, and HNRNPA2B1) was developed using univariate Cox regression and the least absolute shrinkage and selection operator Cox regression methods.ResultsThis established signature demonstrated good predictive efficacy with an area under the curve of 0.892 and 0.731 in the training cohort and the validation cohort, respectively. Patients with AML and an increased level of Insulin growth factor 2 mRNA binding protein 3 (IGF2BP3) expression exhibited a poor prognosis. IGF2BP3 knockdown significantly induced G0/G1 phase arrest and inhibited cell proliferation, apoptosis, and/or differentiation. Further, the JAK/STAT pathway may be involved in the regulation of EPOR expression by IGF2BP3-mediated m6A RNA methylation.ConclusionThese findings indicate that IGF2BP3 plays a carcinogenic role in AML, implying that it can predict patient survival and could be an effective strategy for AML therapy.
| S-EPMC10474828 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most prevalent internal mRNA modification. m6A can be installed by the methyltransferase complex and removed by demethylases, which are involved in regulating post-transcriptional expression of target genes. RNA methylation is linked to various inflammatory states, including autoimmunity, infection, metabolic disease, cancer, neurodegenerative diseases, heart diseases, and bone diseases. However, systematic knowledge of the relationship between m6A modification and inflammation in human diseases remains unclear. In this review, we will discuss the association between m6A modification and inflammatory response in diseases, especially the role, mechanisms, and potential clinical application of m6A as a biomarker and therapeutic target for inflammatory diseases.
| S-EPMC8213350 | biostudies-literature
Project description:This study was conducted to investigate effect of N6-methyladenosine (m6A) RNA methylation on Heat shock proteins (HSPs) and dissect the profile of HSP RNA methylation. The results showed that m6A methyltransferases METTL3 mRNA was decreased in responses to heat shock stress in HepG2 cells, but m6A-specific binding protein YTHDF2 mRNA was upregulated in a manner similar to HSP70 induction. Immunofluorescence staining showed that the majority of YTHDF2 was present in the cytosol, however, nearly all YTHDF2 translocated from the cytosol into the nucleus after heat shock. METTL3 knockdown significantly changed HSP70, HSP60, and HSP27 mRNA expression in HepG2 cells using siRNA, however, mRNA lifetime was not impacted. Silence of YTHDF2 using siRNA did not change expression of HSP70, but significantly increased HSP90, HSP60, and HSPB1 mRNA expression. In addition, m6A-seq revealed that HSP m6A methylation peaks are mainly enriched on exons and around stop codons, and shows a unique distribution profile in the 5'UTR and 3'UTR. Knockdown of METTL3 changed the methylation patterns of HSPs transcript. In conclusion, m6A RNA methylation regulates HSP gene expression. Differential expression of HSPs modulated by m6A may depend on the m6A site and abundance of the target gene. This finding provides insights into new regulatory mechanisms of HSPs in normal and stress situations.
| S-EPMC6002042 | biostudies-literature
Project description:RNA methylations are essential both for RNA structure and function, and are introduced by a number of distinct methyltransferases (MTases). In recent years, N6-methyladenosine (m6A) modification of eukaryotic mRNA has been subject to intense studies, and it has been demonstrated that m6A is a reversible modification that regulates several aspects of mRNA function. However, m6A is also found in other RNAs, such as mammalian 18S and 28S ribosomal RNAs (rRNAs), but the responsible MTases have remained elusive. 28S rRNA carries a single m6A modification, found at position A4220 (alternatively referred to as A4190) within a stem-loop structure, and here we show that the MTase ZCCHC4 is the enzyme responsible for introducing this modification. Accordingly, we found that ZCCHC4 localises to nucleoli, the site of ribosome assembly, and that proteins involved in RNA metabolism are overrepresented in the ZCCHC4 interactome. Interestingly, the absence of m6A4220 perturbs codon-specific translation dynamics and shifts gene expression at the translational level. In summary, we establish ZCCHC4 as the enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation.
| S-EPMC6954407 | biostudies-literature