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Genes Mar 2021Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator... (Review)
Review
Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl channel. Loss of Cl secretion across the apical membrane of airway lining epithelial cells results in dehydration of the airway surface liquid (ASL) layer which impairs mucociliary clearance (MCC), and as a consequence promotes bacterial infection and inflammation of the airways. Interventions that restore airway hydration are known to improve MCC. Here we review the ion channels present at the luminal surface of airway epithelial cells that may be targeted to improve airway hydration and MCC in CF airways.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Loss of Function Mutation; Mucociliary Clearance; Respiratory Mucosa
PubMed: 33810137
DOI: 10.3390/genes12030453 -
Medicine Apr 2023Merkel cell carcinoma (MCC), a rare primary cutaneous neuroendocrine neoplasm, is extremely aggressive and has a higher mortality rate than melanoma. Based on Merkel... (Review)
Review
Merkel cell carcinoma (MCC), a rare primary cutaneous neuroendocrine neoplasm, is extremely aggressive and has a higher mortality rate than melanoma. Based on Merkel cell polyomavirus (MCPyV) status and morphology, MCCs are often divided into several distinct subsets: pure MCPyV-positive, pure MCPyV-negative, and combined MCC. MCPyV-positive MCC develops by the clonal integration of viral DNA, whereas MCPyV-negative MCC is induced by frequent ultraviolet (UV)-mediated mutations, that are characterized by a high mutational burden, UV signature mutations, and many mutations in TP53 and retinoblastoma suppressor gene (RB1). Combined MCC consists of an intimate mix of MCC and other cutaneous tumor populations, and is usually MCPyV-negative, with rare exceptions. Based on the existing subsets of MCC, it is speculated that there are at least 4 stages in the natural history of stem cell differentiation: primitive pluripotent stem cells, divergent differentiated stem cells, unidirectional stem cells, and Merkel cells (or epidermal/adnexal cells). In the first stage, MCPyV may integrate into the genome of primitive pluripotent stem cells, driving oncogenesis in pure MCPyV-positive MCC. If MCPyV integration does not occur, the stem cells enter the second stage and acquire the ability to undergo multidirectional neuroendocrine and epidermal (or adnexal) differentiation. At this stage, accumulated UV-mediated mutations may drive the development of combined MCC. In the third stage, the stem cells differentiate into unidirectional neuroendocrine stem cells, UV-mediated mutations can induce carcinogenesis in pure MCPyV-negative MCC. Therefore, it has been speculated that several subsets of MCCs arise from different stages of differentiation of common stem cells.
Topics: Humans; Carcinoma, Merkel Cell; Skin Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; Stem Cells; Cell Differentiation; Merkel cell polyomavirus; Polyomavirus Infections; Tumor Virus Infections
PubMed: 37058042
DOI: 10.1097/MD.0000000000033535 -
Genes Aug 2022Identification of miRNA-mRNA interactions is critical to understand the new paradigms in gene regulation. Existing methods show suboptimal performance owing to...
Identification of miRNA-mRNA interactions is critical to understand the new paradigms in gene regulation. Existing methods show suboptimal performance owing to inappropriate feature selection and limited integration of intuitive biological features of both miRNAs and mRNAs. The present regularized least square-based method, mintRULS, employs features of miRNAs and their target sites using pairwise similarity metrics based on free energy, sequence and repeat identities, and target site accessibility to predict miRNA-target site interactions. We hypothesized that miRNAs sharing similar structural and functional features are more likely to target the same mRNA, and conversely, mRNAs with similar features can be targeted by the same miRNA. Our prediction model achieved an impressive AUC of 0.93 and 0.92 in LOOCV and LmiTOCV settings, respectively. In comparison, other popular tools such as miRDB, TargetScan, MBSTAR, RPmirDIP, and STarMir scored AUCs at 0.73, 0.77, 0.55, 0.84, and 0.67, respectively, in LOOCV setting. Similarly, mintRULS outperformed other methods using metrics such as accuracy, sensitivity, specificity, and MCC. Our method also demonstrated high accuracy when validated against experimentally derived data from condition- and cell-specific studies and expression studies of miRNAs and target genes, both in human and mouse.
Topics: Animals; Gene Expression Regulation; Humans; Least-Squares Analysis; Mice; MicroRNAs; RNA, Messenger
PubMed: 36140696
DOI: 10.3390/genes13091528 -
Journal of Translational Medicine Dec 2021Osteoarthritis (OA), which is due to the progressive loss and degeneration of articular cartilage, is the leading cause of disability worldwide. Therefore, it is of...
BACKGROUND
Osteoarthritis (OA), which is due to the progressive loss and degeneration of articular cartilage, is the leading cause of disability worldwide. Therefore, it is of great significance to explore OA biomarkers for the prevention, diagnosis, and treatment of OA.
METHODS AND MATERIALS
The GSE129147, GSE57218, GSE51588, GSE117999, and GSE98918 datasets with normal and OA samples were downloaded from the Gene Expression Omnibus (GEO) database. The GSE117999 and GSE98918 datasets were integrated, and immune infiltration was evaluated. The differentially expressed genes (DEGs) were analyzed using the limma package in R, and weighted gene co-expression network analysis (WGCNA) was used to explore the co-expression genes and co-expression modules. The co-expression module genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and hub genes were identified by the degree, MNC, closeness, and MCC algorithms. The hub genes were used to construct a diagnostic model based on support vector machines.
RESULTS
The Immune Score in the OA samples was significantly higher than in the normal samples, and a total of 2313 DEGs were identified. Through WGCNA, we found that the yellow module was significantly positively correlated with the OA samples and Immune Score and negatively correlated with the normal samples. The 142 DEGs of the yellow module were related to biological processes such as regulation of inflammatory response, positive regulation of inflammatory response, blood vessel morphogenesis, endothelial cell migration, and humoral immune response. The intersections of the genes obtained by the 4 algorithms resulted in 5 final hub genes, and the diagnostic model constructed with these 5 genes showed good performance in the training and validation cohorts.
CONCLUSIONS
The 5-gene diagnostic model can be used to diagnose OA and guide clinical decision-making.
Topics: Computational Biology; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Humans; Osteoarthritis; Protein Interaction Maps
PubMed: 34949204
DOI: 10.1186/s12967-021-03183-9 -
RNA Biology 2022The transcription factor p53 exerts its tumour suppressive effect through transcriptional activation of numerous target genes controlling cell cycle arrest, apoptosis,...
The transcription factor p53 exerts its tumour suppressive effect through transcriptional activation of numerous target genes controlling cell cycle arrest, apoptosis, cellular senescence and DNA repair. In addition, there is evidence that p53 influences the translation of specific mRNAs, including translational inhibition of ribosomal protein synthesis and translational activation of MDM2. A challenge in the analysis of translational control is that changes in mRNA abundance exert a kinetic (passive) effect on ribosome densities. In order to separate these passive effects from active regulation of translation efficiency in response to p53 activation, we conducted a comprehensive analysis of translational regulation by comparative analysis of mRNA levels and ribosome densities upon DNA damage induced by neocarzinostatin in wild-type and TP53 HCT116 colorectal carcinoma cells. Thereby, we identified a specific group of mRNAs that are preferentially translated in response to p53 activation, many of which correspond to p53 target genes including MDM2, SESN1 and CDKN1A. By subsequent polysome profile analysis of SESN1 and CDKN1A mRNA, we could demonstrate that p53-dependent translational activation relies on a combination of inducing the expression of translationally advantageous isoforms and -acting mechanisms that further enhance the translation of these mRNAs.
Topics: Cell Cycle Checkpoints; Gene Expression Regulation; Humans; RNA, Messenger; Ribosomes; Transcription Factors; Tumor Suppressor Protein p53
PubMed: 35388737
DOI: 10.1080/15476286.2022.2048562 -
Biomedicine & Pharmacotherapy =... Oct 2021MicroRNAs play an important role in health and disease. TGF-β signaling, upregulated by HIV Tat, and in chronic airway diseases and smokers upregulates miR-145-5p to...
BACKGROUND
MicroRNAs play an important role in health and disease. TGF-β signaling, upregulated by HIV Tat, and in chronic airway diseases and smokers upregulates miR-145-5p to suppress cystic fibrosis transmembrane conductance regulator (CFTR). CFTR suppression in chronic airway diseases like Cystic Fibrosis, COPD and smokers has been associated with suppressed MCC and recurrent lung infections and inflammation. This can explain the emergence of recurrent lung infections and inflammation in people living with HIV.
METHODS
Tat-induced aberrant microRNAome was identified by miRNA expression analysis. microRNA mimics and antagomirs were used to validate the identified miRNAs involved in Tat mediated CFTR mRNA suppression. CRISPR-based editing of the miRNA target sites in CFTR 3'UTR was used to determine rescue of CFTR mRNA and function in airway epithelial cell lines and in primary human bronchial epithelial cells exposed to TGF-β and Tat.
FINDINGS
HIV Tat upregulates miR-145-5p and miR-509-3p. The two miRNAs demonstrate co-operative effects in suppressing CFTR. CRISPR-based editing of the miRNA target site preserves CFTR mRNA and function in airway epithelial cells INTERPRETATION: Given the important roles of TGF-β signaling and the multitude of genes regulated by miRNAs, we demonstrate that CRISPR-based gene-specific microRNA antagonism approach can preserve CFTR mRNA and function in the context of HIV Tat and TGF-β signaling without suppressing expression of other genes regulated by miR-145-5p.
Topics: 3' Untranslated Regions; Bronchi; CRISPR-Cas Systems; Cell Line; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Gene Editing; Humans; MicroRNAs; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Up-Regulation; tat Gene Products, Human Immunodeficiency Virus
PubMed: 34463266
DOI: 10.1016/j.biopha.2021.112090 -
Frontiers in Genetics 2022Crohn's disease (CD) is a disease that manifests mainly as chronic inflammation of the gastrointestinal tract, which is still not well understood in terms of its...
Crohn's disease (CD) is a disease that manifests mainly as chronic inflammation of the gastrointestinal tract, which is still not well understood in terms of its pathogenesis. The aim of this study was to use bioinformatics analysis to identify differentially expressed genes (DEGs) and miRNAs with diagnostic and therapeutic potential in CD. Three CD datasets (GSE179285, GSE102133, GSE75214) were downloaded from the Gene Expression Omnibus (GEO) database. DEGs between normal and CD tissues were identified using the GEO2R online tool. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were conducted using the clusterProfiler function in the R package. Protein-protein interaction network (PPI) analysis and visualization were performed with STRING and Cytoscape. Ten hub genes were identified using cytoHubba's MCC algorithm and validated with datasets GSE6731 and GSE52746. Finally, the miRNA gene regulatory network was constructed by Cytoscape and NetworkAnalyst to predict potential microRNAs (miRNAs) associated with DEGs. A total of 97 DEGs were identified, consisting of 88 downregulated genes and 9 upregulated genes. The enriched functions and pathways of the DEGs include immune system process, response to stress, response to cytokine and extracellular region. KEGG pathway analysis indicates that the genes were significantly enriched in Cytokine-cytokine receptor interaction, IL-17 signaling pathway, Rheumatoid arthritis and TNF signaling pathway. In combination with the results of the protein-protein interaction (PPI) network and CytoHubba, 10 hub genes including IL1B, CXCL8, CXCL10, CXCL1, CXCL2, CXCL5, ICAM1, IL1RN, TIMP1 and MMP3 were selected. Based on the DEG-miRNAs network construction, 5 miRNAs including hsa-mir-21-5p, hsa-mir-93-5p, hsa-mir-98-5p, hsa-mir-1-3p and hsa-mir-335-5p were identified as potential critical miRNAs. In conclusion, a total of 97 DEGs, 10 hub genes and 5 miRNAs that may be involved in the progression or occurrence of CD were identified in this study, which could be regarded as biomarkers of CD.
PubMed: 36118873
DOI: 10.3389/fgene.2022.950136 -
Frontiers in Physiology 2022We aim to explore the detailed molecular mechanisms of membrane nephropathy (MN) related genes by bioinformatics analysis. Two microarray datasets (GSE108109 and...
We aim to explore the detailed molecular mechanisms of membrane nephropathy (MN) related genes by bioinformatics analysis. Two microarray datasets (GSE108109 and GSE104948) with glomerular gene expression data from 65 MN patients and 9 healthy donors were obtained from the Gene Expression Omnibus (GEO) database. After processing the raw data, DEGs screening was conducted using the LIMMA (linear model for microarray data) package and Gene set enrichment analysis (GSEA) was performed with GSEA software (v. 3.0), followed by gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The protein-protein interaction (PPI) network analysis was carried out to determine the hub genes, by applying the maximal clique centrality (MCC) method, which was visualized by Cytoscape. Finally, utilizing the Nephroseq v5 online platform, we analyzed subgroups associated with hub genes. The findings were further validated by immunohistochemistry (IHC) staining in renal tissues from MN or control patients. A sum of 370 DEGs (188 up-regulated genes, 182 down-regulated genes) and 20 hub genes were ascertained. GO and KEGG enrichment analysis demonstrated that DEGs of MN were preponderantly associated with cell damage and complement cascade-related immune responses. Combined with literature data and hub gene-related MN subset analysis, CTSS, ITGB2, and HCK may play important roles in the pathological process of MN. This study identified novel hub genes in MN using bioinformatics. We found that some hub genes such as CTSS, ITGB2, and HCK might contribute to MN immunopathological process, providing new insights for further study of the molecular mechanisms underlying glomerular injury of MN.
PubMed: 35812314
DOI: 10.3389/fphys.2022.914382 -
Cell Death & Disease Mar 2023Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain,...
Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.
Topics: Animals; Nuclear Proteins; Gene Expression Regulation; Cell Differentiation; Mammals
PubMed: 36932059
DOI: 10.1038/s41419-023-05720-4 -
Gene Reports Jun 2022The coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 is ongoing. Individuals with sarcoidosis tend to develop severe COVID-19; however, the underlying...
The coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 is ongoing. Individuals with sarcoidosis tend to develop severe COVID-19; however, the underlying pathological mechanisms remain elusive. To determine common transcriptional signatures and pathways between sarcoidosis and COVID-19, we investigated the whole-genome transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with COVID-19 and sarcoidosis and conducted bioinformatic analysis, including gene ontology and pathway enrichment, protein-protein interaction (PPI) network, and gene regulatory network (GRN) construction. We identified 33 abnormally expressed genes that were common between COVID-19 and sarcoidosis. Functional enrichment analysis showed that these differentially expressed genes were associated with cytokine production involved in the immune response and T cell cytokine production. We identified several hub genes from the PPI network encoded by the common genes. These hub genes have high diagnostic potential for COVID-19 and sarcoidosis and can be potential biomarkers. Moreover, GRN analysis identified important microRNAs and transcription factors that regulate the common genes. This study provides a novel characterization of the transcriptional signatures and biological processes commonly dysregulated in sarcoidosis and COVID-19 and identified several critical regulators and biomarkers. This study highlights a potential pathological association between COVID-19 and sarcoidosis, establishing a theoretical basis for future clinical trials.
PubMed: 35317263
DOI: 10.1016/j.genrep.2022.101597