Do lncRNAs and circRNAs expression profiles influence discoid lupus erythematosus progression?-a comprehensive analysis.
ABSTRACT: Background:Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs)are involved in the progression of discoid lupus erythematosus (DLE), but an understanding of their underlying mechanisms remains elusive. To explore the expression profiles of lncRNAs and circRNAs in DLE, we surveyed the lncRNA/circRNA and mRNA expression profiles in the epithelia of oral DLE and adjacent normal tissues. Methods:The lesional and non-lesional lower lips of three DLE patients were analysed by RNA-sequencing (RNA-seq). The principal functions of the significantly deregulated genes were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. And the correlated expression networks (coding-noncoding co-expression and lncRNAs-transcription factor-mRNA) were evaluated as well. Results:Hundreds of significantly changed lncRNAs and mRNAs and dozens of significantly changed circRNAs were identified. lncRNA lnc-MIPOL1-6 and IncRNA IncDDX47-3 expressions were correlated with immune response-related genes, including IL19, CXCL1, CXCL11, and TNFSF15. Up-regulated IncRNA-TF network consists of 8 TFs and 74 related lncRNAs. The lncRNA-TF-gene trans-regulation consisting of 204 lncRNAs,39 TFs, and correlated 3 genes. Conclusions:These results demonstrate that lncRNAs and circRNAs can influence the progression of DLE. Certain mRNAs/lncRNAs/circRNAs may have substantial value in DLE diagnosis and therapy.
Project description:Advances in developmental cardiology have increased our understanding of the early aspects of heart differentiation. However, understanding noncoding RNA (ncRNA) transcription and regulation during this process remains elusive. Here, we constructed transcriptomes for both long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in four important developmental stages ranging from early embryonic to cardiomyocyte based on high-throughput sequencing datasets, which indicate the high stage-specific expression patterns of two ncRNA types. Additionally, higher similarities of samples within each stage were found, highlighting the divergence of samples collected from distinct cardiac developmental stages. Next, we developed a method to identify numerous lncRNA and circRNA regulators whose expression was significantly stage-specific and shifted gradually and continuously during heart differentiation. We inferred that these ncRNAs are important for the stages of cardiac differentiation. Moreover, transcriptional regulation analysis revealed that the expression of stage-specific lncRNAs is controlled by known key stage-specific transcription factors (TFs). In addition, circRNAs exhibited dynamic expression patterns independent from their host genes. Functional enrichment analysis revealed that lncRNAs and circRNAs play critical roles in pathways that are activated specifically during heart differentiation. We further identified candidate TF-ncRNA-gene network modules for each differentiation stage, suggesting the dynamic organization of lncRNAs and circRNAs collectively controlled cardiac differentiation, which may cause heart-related diseases when defective. Our study provides a foundation for understanding the dynamic regulation of ncRNA transcriptomes during heart differentiation and identifies the dynamic organization of novel key lncRNAs and circRNAs to collectively control cardiac differentiation.
Project description:This article contains data related to the research article entitled "Systematic analysis reveals long noncoding RNAs regulating neighboring transcription factors in human cancers" (Liu et al., 2018 in press) . Long noncoding RNAs (lncRNAs) are proposed to play essential roles in modulating the expression of the nearby loci. In this study, we systematically investigated the relationship between lncRNAs and their neighboring genes based on the genomic location of genes and the transcriptome expression profiles from TCGA samples across 12 tumor types. Position conservation analysis was applied to find lncRNAs conserved by position across vertebrate species. Gene ontology and enrichment analysis identified TF genes as a specific type of protein-coding genes that adjacent to highly positionally conserved lncRNA. The expression correlation of lncRNAs and their adjacent TFs were assessed across tumors to define significant co-expressed lncRNA-TF pairs, and a causal inference test (CIT) was used to infer the causal regulation of lncRNA on its nearby TF genes. A list of candidate lncRNA/TF regulation pairs in tumors was provided.
Project description:Increasing data demonstrate that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. However, the mechanisms in colorectal cancer (CRC) remain unclear. Here, hundreds of significantly expressed circRNAs, and thousands of lncRNAs as well as mRNAs were identified. By qRT-PCR, one abnormal circRNA, lncRNA, and three mRNAs were verified in 24 pairs of tissues and blood samples, respectively. Then, by GO analysis, we found that the gene expression profile of linear counterparts of upregulated circRNAs in human CRC tissues preferred positive regulation of GTPase activity, cellular protein metabolic process, and protein binding, while that of downregulated circRNAs of CRC preferred positive regulation of cellular metabolic process, acetyl-CoA metabolic process, and protein kinase C activity. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that p53 signaling pathway was an important pathway in upregulated protein-coding genes, whereas cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway was the top enriched KEGG pathway for downregulated transcripts. Furthermore, lncRNA-mRNA co-expression analysis demonstrated that downregulated lncRNA uc001tma.3 was negatively with CDC45 and positively with ELOVL4, BVES, FLNA, and HSPB8, while upregulated lncRNA NR_110882 was positively with FZD2. In addition, lncRNA-transcription factor (TF) co-expression analysis showed that the most relevant TFs were forkhead box protein A1 (FOXA1), transcription initiation factor TFIID submint 7 (TAF7), and adenovirus early region 1A(E1A)-associated protein p300 (EP300). Our findings offer a fresh view on circRNAs and lncRNAs and provide the foundation for further study on the potential roles of circRNAs and lncRNAs in colorectal cancer.
Project description:Accumulating evidence indicates that long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) involve in germ cell development. However, little is known about the functions and mechanisms of lncRNAs and circRNAs in self-renewal and differentiation of germline stem cells. Therefore, we explored the expression profiles of mRNAs, lncRNAs, and circRNAs in male and female mouse germline stem cells by high-throughput sequencing. We identified 18573 novel lncRNAs and 18822 circRNAs in the germline stem cells and further confirmed the existence of these lncRNAs and circRNAs by RT-PCR. The results showed that male and female germline stem cells had similar GDNF signaling mechanism. Subsequently, 8115 mRNAs, 3996 lncRNAs, and 921 circRNAs exhibited sex-biased expression that may be associated with germline stem cell acquisition of the sex-specific properties required for differentiation into gametes. Gene Ontology (GO) and KEGG pathway enrichment analyses revealed different functions for these sex-biased lncRNAs and circRNAs. We further constructed correlated expression networks including coding-noncoding co-expression and competing endogenous RNAs with bioinformatics. Co-expression analysis showed hundreds of lncRNAs were correlated with sex differences in mouse germline stem cells, including lncRNA Gm11851, lncRNA Gm12840, lncRNA 4930405O22Rik, and lncRNA Atp10d. CeRNA network inferred that lncRNA Meg3 and cirRNA Igf1r could bind competitively with miRNA-15a-5p increasing target gene Inha, Acsl3, Kif21b, and Igfbp2 expressions. These findings provide novel perspectives on lncRNAs and circRNAs and lay a foundation for future research into the regulating mechanisms of lncRNAs and circRNAs in germline stem cells.
Project description:A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors (TFs) across the genome, but how these lncRNA-TF gene duplexes regulate tissue development and homeostasis is unclear. We identified a feedback loop within the NANCI (Nkx2.1-associated noncoding intergenic RNA)-Nkx2.1 gene duplex that is essential for buffering Nkx2.1 expression, lung epithelial cell identity, and tissue homeostasis. Within this locus, Nkx2.1 directly inhibits NANCI, while NANCI acts in cis to promote Nkx2.1 transcription. Although loss of NANCI alone does not adversely affect lung development, concurrent heterozygous mutations in both NANCI and Nkx2.1 leads to persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate. This disruption in the NANCI-Nkx2.1 gene duplex results in a defective perinatal innate immune response, tissue damage, and progressive degeneration of the adult lung. These data point to a mechanism in which lncRNAs act as rheostats within lncRNA-TF gene duplex loci that buffer TF expression, thereby maintaining tissue-specific cellular identity during development and postnatal homeostasis.
Project description:Obliterative bronchiolitis (OB) is characterized by sub-epithelial inflammatory and fibrotic narrowing of the bronchioles, and it is the predominant factor limiting long-term survival after lung transplantation. To explore molecular mechanism of OB, we investigated the interaction of transcription factor (TF), microRNA, long noncoding RNA (lncRNA), and gene expression in the mice model of OB by integrated analysis of TF array, miRNA microarray, and lncRNA and mRNA microarray. After 28 days of orthotopic tracheal transplantation in mice, 42 TFs were significantly up-regulated in allogeneic graft compared to syngeneic graft; 62 miRNAs including miR-376-5p were up-regulated and 17 miRNAs including miR-338-3p were down-regulated over 2-fold; 137 mRNAs were down-regulated and 129 mRNAs were up-regulated over 2-fold; 234 lncRNAs were up-regulated and 212 lncRNAs were down-regulated over 2-fold in the allogeneic model compared to that in the syngeneic control group. We further analyzed potential interaction between TFs, miRNAs, lncRNAs and target genes by different algorithms. Four differentially expressed TFs (Myc/Max, FOXO1, FOXM1, and SMAD) were predicted to regulate 3 different miRNAs, 17 mRNAs, and 16 lncRNAs. These findings suggest that modulation of altered transcription factors such as Myc/Max and FOXO1, and miRNAs such as miR-376-5p and miR-338-3p may become a preventive or therapeutic targets in the chronic lung allograft dysfunction.
Project description:Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in cis to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor-Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.
Project description:The pathological development of ovarian cancer (OC) is a complex progression that depends on multiple alterations of coding and non-coding genes. Therefore, it is important to capture the transcriptional-regulating events during the progression of OC development and to identify reliable markers for predicting clinical outcomes in patients. A dataset of 399 ovarian serous cystadenocarcinoma patients at different stages from The Cancer Genome Atlas (TCGA) was analyzed. Stage-specific transcription factor (TF)-long non-coding RNA (lncRNA) regulatory networks were constructed by integrating high-throughput RNA molecular profiles and TF binding information. Systematic analysis was performed to characterize the TF-lncRNA-regulating behaviors across different stages of OC. Cox regression analysis and Kaplan-Meier survival curves were used to evaluate the prognostic efficiency of TF-lncRNA regulations and cliques. The stage-specific TF-lncRNA regulatory networks at three OC stages (II, III, and IV) exhibited common structures and specific topologies of risk TFs and lncRNAs. A TF-lncRNA activity profile across different stages revealed that TFs were highly stage-selective in regulating lncRNAs. Functional analysis indicated that groups of TF-lncRNA interactions were involved in specific pathological processes in the development of OC. In a STAT3-FOS co-regulating clique, the TFs STAT3 and FOS were selectively regulating target lncRNAs across different OC stages. Further survival analysis indicated that this TF-lncRNA biclique may have the potential for predicting OC prognosis. This study revealed the topological and dynamic principles of TF-lncRNA regulatory networks and provided a resource for further analysis of stage-specific regulating mechanisms of OC.
Project description:Colon cancer is the most commonly diagnosed malignancy and the leading cause of cancer deaths worldwide. As well as lifestyle, genetic and epigenetic changes are key factors that influence the risk of colon cancer. However, the impact of epigenetic alterations in non-coding RNAs and their consequences in colon cancer have not been fully characterized. We detected differential methylation sites (DMSs) in long non-coding RNA (lncRNA) promoters and identified lncRNA expression quantitative trait methylations (lncQTMs) by association tests. To investigate how transcription factor (TF) binding was affected by DNA methylation, we characterized the occurrence of known TFs among DMSs collected from the MEME suite. We further combined methylome and transcriptome data to construct TF-methylation-lncRNA relationships. To study the role of lncRNAs in drug response, we used pharmacological and lncRNA profiles from the Cancer Cell Line Encyclopedia (CCLE) and investigated the association between lncRNAs and drug activity. We also used combinations of TF-methylation-lncRNA relationships to stratify patient survival using a risk model. DNA methylation sites displayed global hyper-methylation in lncRNA promoters and tended to have negative relationships with the corresponding lncRNAs. Negative lncQTMs located near transcription start sites (TSSs) had more significant correlations with the corresponding lncRNAs. Some lncRNAs found to be mediated by the interplay between DNA methylation and TFs were previously identified as markers for colon cancer. We also found that the ELF1-cg05372727- LINC00460 relationship were prognostic signatures for colon cancer. These findings suggest that lncRNAs mediated by the interplay between DNA methylation and TFs are promising predictors of drug response, and that combined TF-methylation-lncRNA can serve as a prognostic signature for colon cancer.
Project description:<b>Aims: </b>Noncoding RNAs (ncRNAs) play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). This paper summarized the current evidences of the involvement microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in the differential expressions and their interaction with each other in T2DM.<br><br><b>Methods: </b>The differentially expressed miRNAs, lncRNAs, and circRNAs in the blood circulation (plasma, serum, whole blood, and peripheral blood mononuclear cells) of patients with T2DM were found in PubMed, GCBI, and other databases. The interactions between ncRNAs were predicted based on the MiRWalk and the DIANA Tools databases. The indirect and direct target genes of lncRNAs and circRNAs were predicted based on the starBase V2.0, DIANA Tools, and LncRNA-Target databases. Then, GO and KEGG analysis on all miRNA, lncRNA, and circRNA target genes was performed using the mirPath and Cluster Profile software package in R language. The lncRNA-miRNA and circRNA-miRNA interaction diagram was constructed with Cytoscape. The aim of this investigation was to construct a mechanism diagram of lncRNA involved in the regulation of target genes on insulin signaling pathways and AGE-RAGE signaling pathways of diabetic complications.<br><br><b>Results: </b>A total of 317 RNAs, 283 miRNAs, and 20 lncRNAs and circRNAs were found in the circulation of T2DM. Dysregulated microRNAs and lncRNAs were found to be involved in signals related to metabolic disturbances, insulin signaling, and AGE-RAGE signaling in T2DM. In addition, lncRNAs participate in the regulation of key genes in the insulin signaling and AGE-RAGE signaling pathways through microRNAs, which leads to insulin resistance and diabetic vascular complications.<br><br><b>Conclusion: </b>Noncoding RNAs participate in the occurrence and development of type 2 diabetes and lead to its vascular complications by regulating different signaling pathways.