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1.
J Virol ; 95(12)2021 05 24.
Article in English | MEDLINE | ID: covidwho-1501541

ABSTRACT

Long disregarded as junk DNA or genomic dark matter, endogenous retroviruses (ERVs) have turned out to represent important components of the antiviral immune response. These remnants of once-infectious retroviruses not only regulate cellular immune activation, but may even directly target invading viral pathogens. In this Gem, we summarize mechanisms by which retroviral fossils protect us from viral infections. One focus will be on recent advances in the role of ERVs as regulators of antiviral gene expression.


Subject(s)
Endogenous Retroviruses/physiology , Retroelements , Virus Diseases/immunology , Animals , Endogenous Retroviruses/genetics , Enhancer Elements, Genetic , Gene Expression Regulation , Humans , Immunity, Cellular , Promoter Regions, Genetic , RNA, Double-Stranded/genetics , RNA, Double-Stranded/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Receptors, Pattern Recognition/metabolism , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , Viral Proteins/metabolism , Virion/metabolism , Virus Diseases/genetics , Virus Diseases/virology
2.
Cells ; 10(10)2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438524

ABSTRACT

The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed the essential contribution of RNA-mediated mechanisms to the regulation of fundamental processes of life. With the recent development of SARS-CoV-2 mRNA-based vaccines, the potential of RNA as a therapeutic tool has received public attention. Due to its intrinsic single-stranded nature and the ease with which it is synthesized in vitro, RNA indeed represents the most suitable tool for the development of drugs encompassing every type of human pathology. The maximum effectiveness and biochemical versatility is achieved in the guise of non-coding RNAs (ncRNAs), which are emerging as multifaceted regulators of tissue specification and homeostasis. Here, we report examples of coding and ncRNAs involved in muscle regeneration and discuss their potential as therapeutic tools. Small ncRNAs, such as miRNA and siRNA, have been successfully applied in the treatment of several diseases. The use of longer molecules, such as lncRNA and circRNA, is less advanced. However, based on the peculiar properties discussed below, they represent an innovative pool of RNA biomarkers and possible targets of clinical value.


Subject(s)
MicroRNAs/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , RNA, Messenger/metabolism , RNA, Untranslated/genetics , Regeneration , Animals , Biomarkers/metabolism , COVID-19 , Homeostasis , Humans , Mice , Muscle, Skeletal/virology , Myocardium/metabolism , Origin of Life , RNA, Circular , RNA, Long Noncoding/genetics , RNA, Small Interfering/metabolism , RNA, Small Untranslated/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics
3.
Physiol Genomics ; 53(10): 433-440, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1398739

ABSTRACT

SARS-CoV-2 harbors many known unknown regions in the form of hypothetical open reading frames (ORFs). Although the mechanisms underlying the disease pathogenesis are not clearly understood, molecules such as long noncoding RNAs (lncRNAs) play a key regulatory role in the viral pathogenesis from endocytosis. We asked whether or not the lncRNAs in the host are associated with the viral proteins and argue that lncRNA-mRNAs molecules related to viral infection may regulate SARS-CoV-2 pathogenesis. Toward the end of the perspective, we provide challenges and insights into investigating these transgression pathways.


Subject(s)
COVID-19/genetics , Host-Pathogen Interactions/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/genetics , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Epitopes , Female , Gene Expression Regulation , Humans , Male , Open Reading Frames , Phylogeny , Protein Interaction Maps , SARS-CoV-2/metabolism , Sex Factors
4.
Mol Oral Microbiol ; 36(6): 291-294, 2021 12.
Article in English | MEDLINE | ID: covidwho-1398524

ABSTRACT

COVID-19, caused by the SARS-CoV-2 virus, has become a significant global public health problem, with a wide variety of clinical manifestations and disease progression outcomes. LncRNAs are key regulators of the immune response and have been associated with COVID-19 risk infection. Previous studies focused mainly on in-silico analysis of lncRNA expression in the lungs or peripheral blood cells. We evaluated the expression of lncRNAs NEAT1, MALAT1, and MIR3142 in saliva and nasopharyngeal swab from SARS-CoV-2 positive (n = 34) and negative patients (n = 46). A higher expression of the lncRNAs NEAT1 and MALAT1 (p < 0.05) were found in positive samples. NEAT1 had a higher expression mainly in saliva samples (p < 0.001), and MALAT1 was upregulated in nasopharyngeal samples (p < 0.05). Area under the ROC curve for NEAT1 in saliva was 0.8067. This study was the first to investigate the expression of lncRNAs in saliva and nasopharyngeal samples of COVID-19 patients, which gives new insights into the initial response to infection and infectivity and may provide new biomarkers for severity and targets for therapy.


Subject(s)
COVID-19 , RNA, Long Noncoding/genetics , Saliva , Humans , Nasopharynx/chemistry , RNA, Long Noncoding/analysis , SARS-CoV-2 , Saliva/chemistry
5.
Nucleic Acids Res ; 49(D1): D916-D923, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-1387963

ABSTRACT

The GENCODE project annotates human and mouse genes and transcripts supported by experimental data with high accuracy, providing a foundational resource that supports genome biology and clinical genomics. GENCODE annotation processes make use of primary data and bioinformatic tools and analysis generated both within the consortium and externally to support the creation of transcript structures and the determination of their function. Here, we present improvements to our annotation infrastructure, bioinformatics tools, and analysis, and the advances they support in the annotation of the human and mouse genomes including: the completion of first pass manual annotation for the mouse reference genome; targeted improvements to the annotation of genes associated with SARS-CoV-2 infection; collaborative projects to achieve convergence across reference annotation databases for the annotation of human and mouse protein-coding genes; and the first GENCODE manually supervised automated annotation of lncRNAs. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.


Subject(s)
COVID-19/prevention & control , Computational Biology/methods , Databases, Genetic , Genomics/methods , Molecular Sequence Annotation/methods , SARS-CoV-2/genetics , Animals , COVID-19/epidemiology , COVID-19/virology , Epidemics , Humans , Internet , Mice , Pseudogenes/genetics , RNA, Long Noncoding/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Transcription, Genetic/genetics
6.
Biomed Res Int ; 2021: 8112783, 2021.
Article in English | MEDLINE | ID: covidwho-1378089

ABSTRACT

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.


Subject(s)
Influenza A virus/pathogenicity , MicroRNAs/genetics , Orthomyxoviridae Infections/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/genetics , Animals , Disease Models, Animal , Disease Susceptibility , Gene Expression Profiling , Influenza A virus/isolation & purification , Interleukin-17/genetics , Interleukin-17/immunology , MicroRNAs/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , RNA, Long Noncoding/immunology , RNA, Messenger/immunology , Rats , Rats, Sprague-Dawley
7.
Adv Clin Exp Med ; 30(8): 839-848, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1359472

ABSTRACT

BACKGROUND: Long non-coding RNAs (lncRNAs) are involved in the development of many cancers, including colorectal cancer (CRC). FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) is a key lncRNA in the regulation of CRC progression, but its potential molecular mechanisms need to be further explored. OBJECTIVES: To investigate the mechanism of lncRNA FEZF1-AS1 in the progression of CRC. MATERIAL AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure FEZF1-AS1 and miR-363-3p expression. Cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 (CCK-8) and transwell assays. Protein expression of epithelial-mesenchymal transformation (EMT)-related markers and paired-related homeobox 1 (PRRX1) were determined using western blot analysis. The interactions among FEZF1-AS1, miR-363-3p and PRRX1 were verified with dual-luciferase reporter assay. A xenograft model was constructed in vivo to confirm the role of FEZF1-AS1 in CRC tumor growth. RESULTS: We demonstrated that FEZF1-AS1 expression was upregulated in CRC, and its silencing reduced CRC cell proliferation, migration, invasion, and EMT. MiR-363-3p could be inhibited by FEZF1-AS1, which inhibitor could reverse the suppressive effect of FEZF1-AS1 silencing on CRC progression. Paired-related homeobox 1 could be targeted by miR-363-3p, and the inhibitory effect of FEZF1-AS1 knockdown on CRC progression could also be eliminated by PRRX1 overexpression. Furthermore, interference of FEZF1-AS1 reduced the tumor growth of CRC in vivo. CONCLUSIONS: Our data demonstrate that FEZF1-AS1 regulated PRRX1 expression to promote CRC progression via inhibition of miR-363-3p.


Subject(s)
Colorectal Neoplasms , MicroRNAs , RNA, Long Noncoding , Cell Proliferation , Colorectal Neoplasms/genetics , Epithelial-Mesenchymal Transition , Homeodomain Proteins , Humans , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Repressor Proteins
8.
Nat Rev Drug Discov ; 20(8): 629-651, 2021 08.
Article in English | MEDLINE | ID: covidwho-1341001

ABSTRACT

Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.


Subject(s)
Genetic Therapy/methods , Molecular Targeted Therapy , Neoplasms/therapy , RNA, Long Noncoding/genetics , Animals , Humans , Neoplasms/genetics
9.
BMC Infect Dis ; 21(1): 588, 2021 Jun 19.
Article in English | MEDLINE | ID: covidwho-1277919

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been shown to cause serious health problems among them is the Acute Respiratory Distress syndrome (ARDS). Vitamin D receptor (VDR) signaling possibly partakes in the pathophysiology of this devastating complication. METHODS: In the current project, we have appraised expression levels of VDR, CYP27B1 and a number of associated lncRNAs in the circulation of COVID-19 patients versus healthy subjects using real-time PCR method. RESULTS: Expression of SNHG6 was considerably lower in COVID-19 patients compared with control subjects (Ratio of mean expression (RME) = 0.22, P value = 7.04E-05) and in both female and male COVID-19 patients compared with sex-matched unaffected individuals (RME = 0.32, P value = 0.04 and RME = 0.16, P value = 0.000679683, respectively). However, its expression was similar among ICU-hospitalized and non-ICU patients. Similarly, expression of SNHG16 was lower in in COVID-19 patients compared with controls (RME = 0.20, P value = 5.94E-05) and in both female and male patients compared with sex-matched controls (RME = 0.32, P value = 0.04 and RME = 0.14, P value = 0.000496435, respectively) with no significant difference among ICU-hospitalized and non-ICU hospitalized patients. Expression of VDR was lower in COVID-19 patients compared with controls (RME = 0.42, P value = 0.04) and in male patients compared with male controls (RME = 0.27, P value = 0.02). Yet, expression of VDR was statistically similar between female subgroups and between ICU-hospitalized and non-ICU hospitalized patients. Expression levels CYP27B, Linc00511 and Linc00346 were similar among COVID-19 patients and healthy subjects or between their subgroups. Significant correlations have been detected between expression levels of VDR, CYP27B and SNHG6, SNHG16, Linc00511 and Linc00346 lncRNAs both among COVID-19 patients and among healthy controls with the most significant ones being SNHG6 and SNHG16 (r = 0.74, P value = 3.26e-17 and r = 0.81, P = 1.54e-22, respectively). CONCLUSION: Combination of transcript levels of VDR, CYP27B and SNHG6, SNHG16, Linc00511 and Linc00346 could differentiate patients from controls with AUC = 0.76, sensitivity = 0.62 and specificity = 0.81. The current data potentiate SNHG6, SNHG16 and VDR as possible contributors in COVID-19 infection but not in the severity of ARDS.


Subject(s)
COVID-19/virology , RNA, Long Noncoding/genetics , Receptors, Calcitriol/genetics , Respiratory Distress Syndrome/virology , SARS-CoV-2/physiology , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Adult , Aged , COVID-19/epidemiology , COVID-19/physiopathology , Case-Control Studies , Female , Humans , Iran/epidemiology , Male , Middle Aged , Pilot Projects , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/physiopathology , Sensitivity and Specificity , Signal Transduction
10.
Cells ; 10(6)2021 06 12.
Article in English | MEDLINE | ID: covidwho-1270010

ABSTRACT

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA-lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA-lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.


Subject(s)
COVID-19/complications , Gene Regulatory Networks , Infertility, Male/virology , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Adult , Angiotensin-Converting Enzyme 2/physiology , COVID-19/genetics , Computational Biology/methods , Computer Simulation , Gene-Environment Interaction , Humans , Infertility, Male/genetics , Male , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/physiology , Testis/metabolism , Testis/pathology , Testis/virology , Virus Internalization
11.
Mediators Inflamm ; 2021: 6635925, 2021.
Article in English | MEDLINE | ID: covidwho-1175215

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the "cytokine storm" of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients (n = 10) and healthy donors (n = 4) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group (p < 0.05). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/genetics , RNA/blood , RNA/genetics , SARS-CoV-2 , Adult , Aged , COVID-19/complications , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/genetics , Cytokines/biosynthesis , Cytokines/genetics , Female , Gene Expression , Humans , Inflammation Mediators/blood , Male , MicroRNAs/blood , MicroRNAs/genetics , Middle Aged , Pandemics , Protein Interaction Maps/genetics , RNA, Long Noncoding/blood , RNA, Long Noncoding/genetics , RNA, Messenger/blood , RNA, Messenger/genetics , Sequence Analysis, RNA , Signal Transduction , Whole Exome Sequencing , Young Adult
12.
Aging (Albany NY) ; 13(5): 6273-6288, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1154950

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. The current coronavirus disease 2019 (COVID-19) shares some similarities with IPF. SARS-CoV-2 related genes have been reported to be broadly regulated by N6-methyladenosine (m6A) RNA modification. Here, we identified the association between m6A methylation regulators, COVID-19 infection pathways, and immune responses in IPF. The characteristic gene expression networks and immune infiltration patterns of m6A-SARS-CoV-2 related genes in different tissues of IPF were revealed. We subsequently evaluated the influence of these related gene expression patterns and immune infiltration patterns on the prognosis/lung function of IPF patients. The IPF cohort was obtained from the Gene Expression Omnibus dataset. Pearson correlation analysis was performed to identify the correlations among genes or cells. The CIBERSORT algorithm was used to assess the infiltration of 22 types of immune cells. The least absolute shrinkage and selection operator (LASSO) and proportional hazards model (Cox model) were used to develop the prognosis prediction model. Our research is pivotal for further understanding of the cellular and genetic links between IPF and SARS-CoV-2 infection in the context of the COVID-19 pandemic, which may contribute to providing new ideas for prognosis assessment and treatment of both diseases.


Subject(s)
Adenosine/analogs & derivatives , COVID-19/genetics , Gene Regulatory Networks , Idiopathic Pulmonary Fibrosis/genetics , Adenosine/genetics , Adenosine/immunology , Algorithms , COVID-19/diagnosis , COVID-19/immunology , Humans , Idiopathic Pulmonary Fibrosis/diagnosis , Idiopathic Pulmonary Fibrosis/immunology , Immunity , Immunity, Cellular , Prognosis , RNA/genetics , RNA/immunology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/immunology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
13.
Viruses ; 13(3)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1125782

ABSTRACT

The recently emerged SARS-CoV-2 virus is responsible for the ongoing COVID-19 pandemic that has rapidly developed into a global public health threat. Patients severely affected with COVID-19 present distinct clinical features, including acute respiratory disorder, neutrophilia, cytokine storm, and sepsis. In addition, multiple pro-inflammatory cytokines are found in the plasma of such patients. Transcriptome sequencing of different specimens obtained from patients suffering from severe episodes of COVID-19 shows dynamics in terms of their immune responses. However, those host factors required for SARS-CoV-2 propagation and the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive. In the present study, we analyzed the mRNA-long non-coding RNA (lncRNA) co-expression network derived from publicly available SARS-CoV-2-infected transcriptome data of human lung epithelial cell lines and bronchoalveolar lavage fluid (BALF) from COVID-19 patients. Through co-expression network analysis, we identified four differentially expressed lncRNAs strongly correlated with genes involved in various immune-related pathways crucial for cytokine signaling. Our findings suggest that the aberrant expression of these four lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection of the lungs. Thus, the present study uncovers molecular interactions behind the cytokine storm activation potentially responsible for hyper-inflammatory responses in critical COVID-19 patients.


Subject(s)
COVID-19/genetics , COVID-19/immunology , RNA, Long Noncoding/genetics , RNA, Messenger/genetics , SARS-CoV-2/physiology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Gene Regulatory Networks , Humans , Lung/immunology , Lung/virology , RNA, Long Noncoding/immunology , RNA, Messenger/immunology , SARS-CoV-2/genetics
14.
Aging (Albany NY) ; 13(5): 6273-6288, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1112911

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. The current coronavirus disease 2019 (COVID-19) shares some similarities with IPF. SARS-CoV-2 related genes have been reported to be broadly regulated by N6-methyladenosine (m6A) RNA modification. Here, we identified the association between m6A methylation regulators, COVID-19 infection pathways, and immune responses in IPF. The characteristic gene expression networks and immune infiltration patterns of m6A-SARS-CoV-2 related genes in different tissues of IPF were revealed. We subsequently evaluated the influence of these related gene expression patterns and immune infiltration patterns on the prognosis/lung function of IPF patients. The IPF cohort was obtained from the Gene Expression Omnibus dataset. Pearson correlation analysis was performed to identify the correlations among genes or cells. The CIBERSORT algorithm was used to assess the infiltration of 22 types of immune cells. The least absolute shrinkage and selection operator (LASSO) and proportional hazards model (Cox model) were used to develop the prognosis prediction model. Our research is pivotal for further understanding of the cellular and genetic links between IPF and SARS-CoV-2 infection in the context of the COVID-19 pandemic, which may contribute to providing new ideas for prognosis assessment and treatment of both diseases.


Subject(s)
Adenosine/analogs & derivatives , COVID-19/genetics , Gene Regulatory Networks , Idiopathic Pulmonary Fibrosis/genetics , Adenosine/genetics , Adenosine/immunology , Algorithms , COVID-19/diagnosis , COVID-19/immunology , Humans , Idiopathic Pulmonary Fibrosis/diagnosis , Idiopathic Pulmonary Fibrosis/immunology , Immunity , Immunity, Cellular , Prognosis , RNA/genetics , RNA/immunology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/immunology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
15.
J Gene Med ; 23(3): e3318, 2021 03.
Article in English | MEDLINE | ID: covidwho-1084739

ABSTRACT

Pulmonary fibrosis is characterized by progressive and irreversible scarring in the lungs with poor prognosis and treatment. It is caused by various factors, including environmental and occupational exposures, and some rheumatic immune diseases. Even the rapid global spread of the COVID-19 pandemic can also cause pulmonary fibrosis with a high probability. Functions attributed to long non-coding RNAs (lncRNAs) make them highly attractive diagnostic and therapeutic targets in fibroproliferative diseases. Therefore, an understanding of the specific mechanisms by which lncRNAs regulate pulmonary fibrotic pathogenesis is urgently needed to identify new possibilities for therapy. In this review, we focus on the molecular mechanisms and implications of lncRNAs targeted protein-coding and non-coding genes during pulmonary fibrogenesis, and systematically analyze the communication of lncRNAs with various types of RNAs, including microRNA, circular RNA and mRNA. Finally, we propose the potential approach of lncRNA-based diagnosis and therapy for pulmonary fibrosis. We hope that understanding these interactions between protein-coding and non-coding genes will contribute to the development of lncRNA-based clinical applications for pulmonary fibrosis.


Subject(s)
Genetic Markers/genetics , Pulmonary Fibrosis/genetics , RNA, Long Noncoding/genetics , Gene Expression Regulation , Genetic Therapy/methods , Humans , MicroRNAs/genetics , Proteins/genetics , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/therapy , RNA, Circular/genetics
16.
Signal Transduct Target Ther ; 5(1): 294, 2020 12 24.
Article in English | MEDLINE | ID: covidwho-997816

ABSTRACT

Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for improving treatment. Here, we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell (PBMC) samples from 18 patients with coronavirus disease 2019 (COVID-19) during their treatment, convalescence, and rehabilitation. After analyzing the regulatory networks of differentially expressed messenger RNAs (mRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) between the different clinical stages, we found that humoral immunity and type I interferon response were significantly downregulated, while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19. The formation of this T cell immune response might be driven by the activation of activating protein-1 (AP-1) related signaling pathway and was weakly affected by other clinical features. These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.


Subject(s)
COVID-19/genetics , Immunity, Humoral/genetics , T-Lymphocytes/metabolism , Transcriptome/genetics , COVID-19/epidemiology , COVID-19/pathology , Female , Humans , Immunity, Humoral/immunology , Leukocytes, Mononuclear/metabolism , Male , MicroRNAs , RNA, Long Noncoding/genetics , RNA-Seq , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transcription Factor AP-1/genetics
17.
Life Sci ; 268: 118959, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-988728

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease which involves the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF involves in the inflammatory processes and is considered as a multisystem disorder that is not confined to lungs, but it also affects other vital organs that leads to numerous co-morbidities. The respiratory disorder in the CF results in mortality and morbidity which is characterized by series of serious events involving mucus hypersecretion, microbial infections, airways obstruction, inflammation, destruction of epithelium, tissue remodeling and terminal lung diseases. Mucins are the high molecular weight glycoproteins important for the viscoelastic properties of the mucus, play a significant role in the disease mechanisms. Determining the functional association between the CFTR and mucins might help to identify the putative target for specific therapeutic approach. In fact, furin enzyme which helps in the entry of novel COVID-19 virus into the cell, is upregulated in CF and this can also serve as a potential target for CF treatment. Moreover, the use of nano-formulations for CF treatment is an area of research being widely studied as they have also demonstrated promising outcomes. The in-depth knowledge of non-coding RNAs like miRNAs and lncRNAs and their functional association with CFTR gene expression and mutation can provide a different range of opportunity to identify the promising therapeutic approaches for CF.


Subject(s)
COVID-19/virology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/physiopathology , Animals , Cystic Fibrosis/genetics , Cystic Fibrosis/therapy , Gene Expression Regulation , Humans , MicroRNAs/genetics , Mucins/metabolism , Mutation , RNA, Long Noncoding/genetics , SARS-CoV-2/pathogenicity
18.
Nucleic Acids Res ; 49(D1): D916-D923, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-955778

ABSTRACT

The GENCODE project annotates human and mouse genes and transcripts supported by experimental data with high accuracy, providing a foundational resource that supports genome biology and clinical genomics. GENCODE annotation processes make use of primary data and bioinformatic tools and analysis generated both within the consortium and externally to support the creation of transcript structures and the determination of their function. Here, we present improvements to our annotation infrastructure, bioinformatics tools, and analysis, and the advances they support in the annotation of the human and mouse genomes including: the completion of first pass manual annotation for the mouse reference genome; targeted improvements to the annotation of genes associated with SARS-CoV-2 infection; collaborative projects to achieve convergence across reference annotation databases for the annotation of human and mouse protein-coding genes; and the first GENCODE manually supervised automated annotation of lncRNAs. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.


Subject(s)
COVID-19/prevention & control , Computational Biology/methods , Databases, Genetic , Genomics/methods , Molecular Sequence Annotation/methods , SARS-CoV-2/genetics , Animals , COVID-19/epidemiology , COVID-19/virology , Epidemics , Humans , Internet , Mice , Pseudogenes/genetics , RNA, Long Noncoding/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Transcription, Genetic/genetics
19.
Front Immunol ; 11: 590870, 2020.
Article in English | MEDLINE | ID: covidwho-902405

ABSTRACT

The COVID-19 pandemic exerts inflammation-related parasympathetic complications and post-infection manifestations with major inter-individual variability. To seek the corresponding transcriptomic origins for the impact of COVID-19 infection and its aftermath consequences, we sought the relevance of long and short non-coding RNAs (ncRNAs) for susceptibility to COVID-19 infection. We selected inflammation-prone men and women of diverse ages among the cohort of Genome Tissue expression (GTEx) by mining RNA-seq datasets from their lung, and blood tissues, followed by quantitative qRT-PCR, bioinformatics-based network analyses and thorough statistics compared to brain cell culture and infection tests with COVID-19 and H1N1 viruses. In lung tissues from 57 inflammation-prone, but not other GTEx donors, we discovered sharp declines of the lung pathology-associated ncRNA DANCR and the nuclear paraspeckles forming neuroprotective ncRNA NEAT1. Accompanying increases in the acetylcholine-regulating transcripts capable of controlling inflammation co-appeared in SARS-CoV-2 infected but not H1N1 influenza infected lung cells. The lung cells-characteristic DANCR and NEAT1 association with inflammation-controlling transcripts could not be observed in blood cells, weakened with age and presented sex-dependent links in GTEx lung RNA-seq dataset. Supporting active involvement in the inflammatory risks accompanying COVID-19, DANCR's decline associated with decrease of the COVID-19-related cellular transcript ACE2 and with sex-related increases in coding transcripts potentiating acetylcholine signaling. Furthermore, transcription factors (TFs) in lung, brain and cultured infected cells created networks with the candidate transcripts, indicating tissue-specific expression patterns. Supporting links of post-infection inflammatory and cognitive damages with cholinergic mal-functioning, man and woman-originated cultured cholinergic neurons presented differentiation-related increases of DANCR and NEAT1 targeting microRNAs. Briefly, changes in ncRNAs and TFs from inflammation-prone human lung tissues, SARS-CoV-2-infected lung cells and man and woman-derived differentiated cholinergic neurons reflected the inflammatory pathobiology related to COVID-19. By shifting ncRNA differences into comparative diagnostic and therapeutic profiles, our RNA-sequencing based Resource can identify ncRNA regulating candidates for COVID-19 and its associated immediate and predicted long-term inflammation and neurological complications, and sex-related therapeutics thereof. Our findings encourage diagnostics of involved tissue, and further investigation of NEAT1-inducing statins and anti-cholinergic medications in the COVID-19 context.


Subject(s)
COVID-19/genetics , Cholinergic Neurons/metabolism , MicroRNAs/genetics , RNA, Long Noncoding/genetics , SARS-CoV-2 , Transcriptome , A549 Cells , Acetylcholine/metabolism , Brain/metabolism , Brain/pathology , COVID-19/virology , Databases, Genetic , Female , Humans , Inflammation/genetics , Influenza A Virus, H1N1 Subtype , Influenza, Human/genetics , Influenza, Human/virology , Lung/metabolism , Lung/pathology , Male , RNA-Seq , Transcription Factors/genetics
20.
Gene ; 762: 145057, 2020 Dec 15.
Article in English | MEDLINE | ID: covidwho-712916

ABSTRACT

COVID-19 is a lurking calamitous disease caused by an unusual virus, SARS-CoV-2, causing massive deaths worldwide. Nonetheless, explicit therapeutic drugs or clinically approved vaccines are not available for COVID-19. Thus, a comprehensive research is crucially needed to decode the pathogenic tools, plausible drug targets, committed to the development of efficient therapy. Host-pathogen interactions via host cellular components is an emerging field of research in this respect. miRNAs have been established as vital players in host-virus interactions. Moreover, viruses have the capability to manoeuvre the host miRNA networks according to their own obligations. Besides protein coding mRNAs, noncoding RNAs might also be targeted in infected cells and viruses can exploit the host miRNA network via ceRNA effect. We have predicted a ceRNA network involving one miRNA (miR-124-3p), one mRNA (Ddx58), one lncRNA (Gm26917) and two circRNAs (Ppp1r10, C330019G07RiK) in SARS-CoV infected cells. We have identified 4 DEGs-Isg15, Ddx58, Oasl1, Usp18 by analyzing a mRNA GEO dataset. There is no notable induction of IFNs and IFN-induced ACE2, significant receptor responsible for S-protein binding mediated viral entry. Pathway enrichment and GO analysis conceded the enrichment of pathways associated with interferon signalling and antiviral-mechanism by IFN-stimulated genes. Further, we have identified 3 noncoding RNAs, playing as potential ceRNAs to the genes associated with immune mechanisms. This integrative analysis has identified noncoding RNAs and their plausible targets, which could effectively enhance the understanding of molecular mechanisms associated with viral infection. However, validation of these targets is further corroborated to determine their therapeutic efficacy.


Subject(s)
Coronavirus Infections/genetics , Gene Regulatory Networks , Host-Pathogen Interactions/genetics , Pneumonia, Viral/genetics , RNA, Circular/genetics , RNA, Long Noncoding/genetics , Animals , Betacoronavirus , COVID-19 , Humans , Mice , MicroRNAs/genetics , Pandemics , Protein Interaction Mapping , RNA, Messenger/genetics , SARS-CoV-2
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