Previous studies have found that ferroptosis plays an important role in a variety of neurological diseases. However, the precise role of ferroptosis in the multiple sclerosis patients remains ...uncertain. We defined and validated a computational metric of ferroptosis levels. The ferroptosis scores were computed using the AUCell method, which reflects the enrichment scores of ferroptosis‐related genes through gene ranking. The reliability of the ferroptosis score was assessed using various methods, involving cells induced to undergo ferroptosis by six different ferroptosis inducers. Through a comprehensive approach integrating snRNA‐seq, spatial transcriptomics, and spatial proteomics data, we explored the role of ferroptosis in multiple sclerosis. Our findings revealed that among seven sampling regions of different white matter lesions, the edges of active lesions exhibited the highest ferroptosis score, which was associated with activation of the phagocyte system. Remyelination lesions exhibit the lowest ferroptosis score. In the cortex, ferroptosis score were elevated in neurons, relevant to a variety of neurodegenerative disease‐related pathways. Spatial transcriptomics demonstrated a significant co‐localization among ferroptosis score, neurodegeneration and microglia, which was verified by spatial proteomics. Furthermore, we established a diagnostic model of multiple sclerosis based on 24 ferroptosis‐related genes in the peripheral blood. Ferroptosis might exhibits a dual role in the context of multiple sclerosis, relevant to both neuroimmunity and neurodegeneration, thereby presenting a promising and novel therapeutic target. Ferroptosis‐related genes in the blood that could potentially serve as diagnostic and prognostic markers for multiple sclerosis.
Abstract
Lnc2Cancer 2.0 (http://www.bio-bigdata.net/lnc2cancer) is an updated database that provides comprehensive experimentally supported associations between lncRNAs and human cancers. In ...Lnc2Cancer 2.0, we have updated the database with more data and several new features, including (i) exceeding a 4-fold increase over the previous version, recruiting 4989 lncRNA-cancer associations between 1614 lncRNAs and 165 cancer subtypes. (ii) newly adding about 800 experimentally supported circulating, drug-resistant and prognostic-related lncRNAs in various cancers. (iii) appending the regulatory mechanism of lncRNA in cancer, including microRNA (miRNA), transcription factor (TF), variant and methylation regulation. (iv) increasing more than 70 high-throughput experiments (microarray and next-generation sequencing) of lncRNAs in cancers. (v) Scoring the associations between lncRNA and cancer to evaluate the correlations. (vi) updating the annotation information of lncRNAs (version 28) and containing more detailed descriptions for lncRNAs and cancers. Moreover, a newly designed, user-friendly interface was also developed to provide a convenient platform for users. In particular, the functions of browsing data by cancer primary organ, biomarker type and regulatory mechanism, advanced search following several features and filtering the data by LncRNA-Cancer score were enhanced. Lnc2Cancer 2.0 will be a useful resource platform for further understanding the associations between lncRNA and human cancer.
Recent studies have suggested that long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) and indirectly regulate miRNA targets though competing interactions. However, the molecular ...mechanisms underlying these interactions are still largely unknown. In this study, these lncRNA-miRNA-gene interactions were defined as lncRNA-associated competing triplets (LncACTs), and an integrated pipeline was developed to identify lncACTs that are active in cancer. Competing lncRNAs had sponge features distinct from non-competing lncRNAs. In the lncACT cross-talk network, disease-associated lncRNAs, miRNAs and coding-genes showed specific topological patterns indicative of their competence and control of communication within the network. The construction of global competing activity profiles revealed that lncACTs had high activity specific to cancers. Analyses of clustered lncACTs revealed that they were enriched in various cancer-related biological processes. Based on the global cross-talk network and cluster analyses, nine cancer-specific sub-networks were constructed. H19- and BRCA1/2-associated lncACTs were able to discriminate between two groups of patients with different clinical outcomes. Disease-associated lncACTs also showed variable competing patterns across normal and cancer patient samples. In summary, this study uncovered and systematically characterized global properties of human lncACTs that may have prognostic value for predicting clinical outcome in cancer patients.
Abstract
Long non-coding RNAs (lncRNAs) that emanate from enhancer regions (defined as enhancer-associated lncRNAs, or elncRNAs) are emerging as critical regulators in disease progression. However, ...their biological characteristics and clinical relevance have not been fully portrayed. Here, based on the traditional expression quantitative loci (eQTL) and our optimized residual eQTL method, we comprehensively described the genetic effect on elncRNA expression in more than 300 lymphoblastoid cell lines. Meanwhile, a chromatin atlas of elncRNAs relative to the genetic regulation state was depicted. By applying the maximum likelihood estimate method, we successfully identified causal elncRNAs for protein-coding gene expression reprogramming and showed their associated single nucleotide polymorphisms (SNPs) favor binding of transcription factors. Further epigenome analysis revealed two immune-associated elncRNAs AL662844.4 and LINC01215 possess high levels of H3K27ac and H3K4me1 in human cancer. Besides, pan-cancer analysis of 3D genome, transcriptome, and regulatome data showed they potentially regulate tumor-immune cell interaction through affecting MHC class I genes and CD47, respectively. Moreover, our study showed there exist associations between elncRNA and patient survival. Finally, we made a user-friendly web interface available for exploring the regulatory relationship of SNP-elncRNA-protein-coding gene triplets (http://bio-bigdata.hrbmu.edu.cn/elncVarReg). Our study provides critical mechanistic insights for elncRNA function and illustrates their implications in human cancer.
Abstract
We describe LncACTdb 2.0 (http://www.bio-bigdata.net/LncACTdb/), an updated and significantly expanded database which provides comprehensive information of competing endogenous RNAs (ceRNAs) ...in different species and diseases. We have updated LncACTdb 2.0 with more data and several new features, including (i) manually curating 2663 experimentally supported ceRNA interactions from >5000 published literatures; (ii) expanding the scope of the database up to 23 species and 213 diseases/phenotypes; (iii) curating more ceRNA types such as circular RNAs and pseudogenes; (iv) identifying and scoring candidate lncRNA-associated ceRNA interactions across 33 cancer types from TCGA data; (v) providing illustration of survival, network and cancer hallmark information for ceRNAs. Furthermore, several flexible online tools including LncACT-Get, LncACT-Function, LncACT-Survival, LncACT-Network and LncACTBrowser have been developed to perform customized analysis, functional analysis, survival analysis, network illustration and genomic visualization. LncACTdb 2.0 also provides newly designed, user-friendly web interfaces to search, browse and download all the data. The BLAST interface is convenient for users to query dataset by inputting custom sequences. The Hot points interface provides users the most studied items by others. LncACTdb 2.0 is a continually updated database and will serve as an important resource to explore ceRNAs in physiological and pathological processes.
Ischemic stroke (IS) is a common and serious neurological disease. Extensive evidence indicates that activation of the immune system contributes significantly to the development of IS pathology. In ...recent years, some long non-coding RNAs (lncRNAs), acting as competing endogenous RNAs (ceRNAs), have been reported to affect IS process, especially the immunological response after stroke. However, the roles of lncRNA-mediated ceRNAs in immune pathogenesis of IS are not systemically investigated. In the present study, we generated a global immune-related ceRNA network containing immune-related genes (IRGs), miRNAs, and lncRNAs based on experimentally verified interactions. Further, we excavated an IS immune-related ceRNA (ISIRC) network through mapping significantly differentially expressed IRGs, miRNAs, and lncRNAs of patients with IS into the global network. We analyzed the topological properties of the two networks, respectively, and found that lncRNA NEAT1 and lncRNA KCNQ1OT1 played core roles in aforementioned two immune-related networks. Moreover, the results of functional enrichment analyses revealed that lncRNAs in the ISIRC network were mainly involved in several immune-related biological processes and pathways. Finally, we identified 17 lncRNAs which were highly related to the immune mechanism of IS through performing random walk with restart for the ISIRC network. Importantly, it has been confirmed that NEAT1, KCNQ1OT1, GAS5, and RMRP could regulate immuno-inflammatory response after stroke, such as production of inflammatory factors and activation of the immune cells. Our results suggested that lncRNAs exerted an important role in the immune pathogenesis of IS and provided a new strategy to do research on IS.
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•Overexpression of microRNA-9a-5p ameliorates ischemic brain injury.•MicroRNA-9a-5p regulates the expression of NLRP1.•MicroRNA-9a-5p influences the NLRP1 inflammasome activation.
The ...nucleotide oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing protein 1 (NLRP1) inflammasome has been shown to contribute to brain injury after ischemic stroke. Our previous study showed that microRNA-9a-5p (miR-9a-5p) ameliorates ischemic injury by regulating neuronal autophagy in rats subjected to middle cerebral artery occlusion (MCAO) surgery. The aims of this study were to investigate whether miR-9a-5p can influence the NLRP1 inflammasome following ischemic stroke and to clarify the mechanism involved. We found that MCAO in rats increased the level of NLRP1 inflammasome proteins, including NLRP1 receptor, ASC and precursor caspase-1, which induced higher levels of cleaved caspase-1, mature interleukin-1β (IL-1β) and interleukin-18 (IL-18). Similarly, the levels of the NLRP1 inflammasome proteins, cleaved caspase-1, mature IL-1β and IL-18 were elevated in SY-5Y cells exposed to oxygen-glucose deprivation (OGD). Further investigation showed that NLRP1 was a target of miR-9a-5p and was downregulated by miR-9a-5p overexpression and upregulated by miR-9a-5p inhibition. Moreover, overexpression of miR-9a-5p not only decreased the levels of NLRP1, ASC and precursor caspase-1 but also reduced the levels of IL-1β and IL-18 in MCAO rats and OGD cells. Therefore, we conclude that miR-9a-5p is involved in NLRP1 inflammasome-mediated ischemic injury, which further suggests that the overexpression of miR-9 may be an effective way to ameliorate brain injury following ischemic stroke.
We developed the Genome Atlas of Breast Cancer (GABC), a global map of noncoding events in the human genome associated with breast cancer that provides a valuable reference resource for users to ...investigate the underlying genome abnormalities in breast cancer patients. Although significant progress has been made in breast cancer treatment, its morbidity and recurrence rates in women are still high worldwide. Curation and integration of breast cancer‐related dysregulations from multiple aspects is essential for disease prevention and diagnosis. In this study, we developed the GABC, which contains 10 172 aberrant noncoding events occurring at multiomics levels, including the genome (single nucleotide polymorphism and somatic mutation), transcriptome (long noncoding RNA and microRNA) and epigenome (DNA methylation, enhancer and superenhancer). Each event entry provides descriptions of detailed biological mechanisms specific to the region or element. Users can also check the genome locations and relationships of functional regulators. The GABC provides a flexible and user‐friendly interface for users to search, browse and download data. In addition, the GABC provides an interface to submit newly discovered noncoding events that can be included in the database. Therefore, the GABC aims to constantly enhance our understanding of noncoding genomic events in breast cancer.
What's new?
Breast cancer is a heterogeneous and complex disease associated with changes in the genome, transcriptome, and epigenome, including in non‐coding regions. However, public resources that focus on non‐coding regions and multi‐omics aspects of breast cancer are still limited. Here, the authors present the Genome Atlas of Breast Cancer (GABC), which contains 10,172 aberrant non‐coding events occurring at the genome (SNP and somatic mutation), transcriptome (lncRNA and miRNA), and epigenome (DNA methylation, enhancer, and super‐enhancer) levels. The GABC provides a user‐friendly multi‐omics interface to search, browse, and download data to better understand the role of non‐coding genomic events in breast cancer.
Abstract
Intertumoral immune heterogeneity is a critical reason for distinct clinical benefits of immunotherapy in lung adenocarcinoma (LUAD). Tumor immunophenotype (immune ‘Hot’ or ‘Cold’) suggests ...immunological individual differences and potential clinical treatment guidelines. However, employing epigenome signatures to determine tumor immunophenotypes and responsive treatment is not well understood. To delineate the tumor immunophenotype and immune heterogeneity, we first distinguished the immune ‘Hot’ and ‘Cold’ tumors of LUAD based on five immune expression signatures. In terms of clinical presentation, the immune ‘Hot’ tumors usually had higher immunoactivity, lower disease stages and better survival outcomes than ‘Cold’ tumors. At the epigenome levels, we observed that distinct DNA methylation patterns between immunophenotypes were closely associated with LUAD development. Hence, we identified a set of five CpG sites as the immunophenotype-related methylation signature (iPMS) for tumor immunophenotyping and further confirmed its efficiency based on a machine learning framework. Furthermore, we found iPMS and immunophenotype-related immune checkpoints (IPCPs) could contribute to the risk of tumor progression, implying IPCP has the potential to be a novel immunotherapy blockade target. After further parsing of the role of iPMS-predicted immunophenotypes, we found immune ‘Hot’ was a protective factor leading to better survival outcomes when patients received the anti-PD-1/PD-L1 immunotherapy. And iPMS was also a well-performed signature (AUC = 0.752) for predicting the durable/nondurable clinical benefits. In summary, our study explored the role of epigenome signature in clinical tumor immunophenotyping. Utilizing iPMS to characterize tumor immunophenotypes will facilitate developing personalized epigenetic anticancer approaches.
Myasthenia gravis (MG) is an autoimmune disease and the most common type of neuromuscular disease. Genes and miRNAs associated with MG have been widely studied; however, the molecular mechanisms of ...transcription factors (TFs) and the relationship among them remain unclear. A TF-miRNA-gene network (TMGN) of MG was constructed by extracting six regulatory pairs (TF-miRNA, miRNA-gene, TF-gene, miRNA-TF, gene-gene and miRNA-miRNA). Then, 3/4/5-node regulatory motifs were detected in the TMGN. Then, the motifs with the highest Z-score, occurring as 3/4/5-node composite feed-forward loops (FFLs), were selected as statistically significant motifs. By merging these motifs together, we constructed a 3/4/5-node composite FFL motif-specific subnetwork (CFMSN). Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MG. In addition, the genes, TFs and miRNAs in the CFMSN were also utilized to identify potential drugs. Five related genes, 3 TFs and 13 miRNAs, were extracted from the CFMSN. As the most important TF in the CFMSN, MYC was inferred to play a critical role in MG. Pathway enrichment analysis showed that the genes and miRNAs in the CFMSN were mainly enriched in pathways related to cancer and infections. Furthermore, 21 drugs were identified through the CFMSN, of which estradiol, estramustine, raloxifene and tamoxifen have the potential to be novel drugs to treat MG. The present study provides MG-related TFs by constructing the CFMSN for further experimental studies and provides a novel perspective for new biomarkers and potential drugs for MG.
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