key: cord-0702763-uftds3sh
authors: Talotta, Rossella; Bahrami, Shervin; Laska, Magdalena Janina
title: Sequence complementarity between human noncoding RNAs and SARS-CoV-2 genes: What are the implications for human health?
date: 2021-10-15
journal: Biochim Biophys Acta Mol Basis Dis
DOI: 10.1016/j.bbadis.2021.166291
sha: 258d2f6de7309d67168d4ddc860877b9909f97f0
doc_id: 702763
cord_uid: uftds3sh

OBJECTIVES: To investigate in silico the presence of nucleotide sequence complementarity between the RNA genome of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and human non-coding (nc)RNA genes. METHODS: The FASTA sequence (NC_045512.2) of each of the 11 SARS-CoV-2 isolate Wuhan-Hu-1 genes was retrieved from NCBI.nlm.nih.gov/gene and the Ensembl.org library interrogated for any base-pair match with human ncRNA genes. SARS-CoV-2 gene-matched human ncRNAs were screened for functional activity using bioinformatic analysis. Finally, associations between identified ncRNAs and human diseases were searched in GWAS databases. RESULTS: A total of 252 matches were found between the nucleotide sequence of SARS-CoV-2 genes and human ncRNAs. With the exception of two small nuclear RNAs, all of them were long non-coding (lnc)RNAs expressed mainly in testis and central nervous system under physiological conditions. The percentage of alignment ranged from 91.30% to 100% with a mean nucleotide alignment length of 17.5 ± 2.4. Thirty-three (13.9%) of them contained predicted R-loop forming sequences, but none of these intersected the complementary sequences of SARS-CoV-2. However, in 31 cases matches fell on ncRNA regulatory sites, whose adjacent coding genes are mostly involved in cancer, immunological and neurological pathways. Similarly, several polymorphic variants of detected non-coding genes have been associated with neuropsychiatric and proliferative disorders. CONCLUSION: This pivotal in silico study shows that SARS-CoV-2 genes have Watson-Crick nucleotide complementarity to human ncRNA sequences, potentially disrupting ncRNA epigenetic control of target genes. It remains to be elucidated whether this could result in the development of human disease in the long term.

loop-forming sequences, which are sites of triple interaction with DNA (RNA-DNA-DNA) that affect chromatin stability and accessibility to the transcriptional machinery [34] . Overall, SARS-CoV-2 gene-complementary human lncRNAs were calculated to form 539 R-loops, which however did not overlap the nucleotide sequence complementary to SARS-CoV-2 genes.

In 31 cases, the complementary SARS-CoV-2 sequences fell into ncRNA regulatory regions (1 open chromatin site; 16 promoter flanks; 4 enhancers; 8 promoters; 1 CTCF-binding site; 1 transcription factor-and CTCFbinding site), Table 2 . Given the epigenetic role played by ncRNAs on the transcription of neighboring genes [35] , we analyzed the flanking chromatin regions of the 31 ncRNAs that matched the SARS-CoV-2 sequences on regulatory sites, by consulting both the Ensembl.org database and the human UCSC Genome Browser GRCh38/hg38. Interestingly, we found that neighboring coding genes, listed in Table 2 , were involved in cancer pathways in 15 cases, regulation of immune response in 10 cases, neurogenesis and nervous system health in 7 cases, metabolic processes in 6 cases, cardiovascular physiology in 5 cases, lung physiology in 3 cases, and mineralization and striated muscle function in 2 and 1 cases, respectively, Figure 1 .

RNAct analysis performed for the 252 ncRNA transcripts revealed that the most plausible protein interactions occurring within the SARS-CoV-2-matching sequences were with the onco-suppressors nischarin (NISH, mean predicted score 25.1 ± 10.2) and AE Binding Protein 2 (AEBP2, mean predicted score 22.8±6.2), whereas lesser interactions (total predicted score 15.1±4.7) were found with the proteins Proline, Glutamate And Leucine Rich Table 3 . Importantly, all these proteins except CHIC1 have been associated with cancer risk and prognosis, as they may act as silencers or enhancers of genes responsible for cell proliferation, differentiation, apoptosis and migration [36] [37] [38] [39] [40] [41] [42] . On the other hand, hyperexpression of CHIC1 has been reported in salivary glands of patients with Sjögren's syndrome [43] , therefore representing a potential autoimmunity biomarker.

SARS-CoV-2 spike mRNA and this event would be of critical importance in the development of pulmonary complications given the role of H19 in the pathogenesis of pulmonary arterial hypertension [53] . In some cases, lncRNAs may induce the potentiation of immune pathways leading to an antiviral response and, in predisposed individuals, autoimmunity or autoinflammation. Indeed, studies have shown that many lncRNAs are highly expressed in CD4+ and CD8+ T lymphocytes and can upset the T helper (Th)1/Th2 cell subpopulations [47] . In addition, some lncRNAs may control macrophage polarization [54] and Th17 cell differentiation [55] .

Following this theory, it could be hypothesized that the immune-mediated manifestations observed in some patients with COVID-19 result in part from the formation of lncRNAs that activate pro-inflammatory pathways.

A few lncRNAs present in our database have been associated with immune mechanisms involved in the antiviral response. The two lncRNAs SLFN12L and NUTM2A-AS1, which correspond to ORF6, have been reported to be involved in the control of either innate or acquired immunity. Specifically, SLFN12L may be induced by type I interferon (IFN) and is typically downregulated during T-cell activation [56] , while NUTM2A-AS1 may modulate the expression of the High-Mobility Group Box 1 (HMGB1) protein secreted by monocyte/macrophage cells in response to pathogens [57] . Regarding B-cell immunity, it has been shown that the lncRNA FAM30A, which contains a complementary sequence to the ORF7a gene, upregulates antibody production and can influence the response to vaccines [58] . Finally, a very recent work demonstrated an association between the lncRNA LINC00278, which matches SARS-CoV-2 ORF7b gene, and the severity of respiratory syncytial virus (RSV)-induced viral bronchiolitis [59] . On this basis, it may be postulated that complementation of human ncRNA to the SARS-CoV-2 genome redirects both innate and acquired immunity in a manner that favors SARS-CoV-2 replication.

In addition, viruses can control the expression of lncRNAs involved in metabolic pathways that are beneficial for their survival. In this context, recent research has described the role of the lncRNA ACOD1 in promoting viral replication. Virus-induced upregulation of ACOD1 may actually promote infection by increasing the activity of the metabolic enzyme glutamic-oxaloacetic transaminase 2 (GOT2) via an IFN-independent mechanism [60] . Importantly, ACOD1 was not annotated in our list and to our knowledge its association with COVID-19 remains unexplored.

Finally, epigenetic crosstalk between virus and host may also promote carcinogenesis in the long term. A recent paper demonstrated the upregulation of the lncRNA CDKN2B-AS1, matching ORF6 in our analysis, in tissue sections from human papillomavirus (HPV)-positive individuals with head and neck squamous cell carcinoma J o u r n a l P r e -p r o o f compared to controls [61] , providing intriguing insight about the link between SARS-CoV-2 infection and tumorigenesis.

With respect to COVID-19, a number of papers show an aberrant expression of lncRNAs in infected individuals [21] [22] [23] . These data are consistent with the results of a deep-sequencing study performed in an animal model of SARS-CoV infection and support the hypothesis that lncRNA transcription may represent a common tract of cellular response to viral infection, which is in turn related to the potentiation of innate immunity [62] . In subjects with COVID-19, GO-analysis showed that hyper-expressed lncRNAs can have a broad spectrum of action in cis-or in trans-regulation. They direct Wingless-related integration site (Wnt)/β-catenin and IL-1mediated signaling pathways, control protein synthesis, transport, phosphorylation and degradation as well as autophagy, angiogenesis and migration of fibroblasts and immune cells [63] . A whole transcriptome study conducted on peripheral blood mononuclear cells (PBMCs) collected from COVID-19 patients during treatment, convalescence and rehabilitation found 405 differentially expressed lncRNAs that included CCNT2-AS1, SLFN12L, NUTM2A-AS1, LMCD1-AS1 and POC1B-AS1, which were also found in our analysis [64] .

Although none of them was significantly associated with a specific disease stage, the results showed the hyperexpression of the snRNA RNVU1-4, which corresponds to the SARS-CoV-2 gene ORF6, during recovery.

SARS-CoV-2-infected patients with more severe course of disease typically show lymphopenia with exhaustion of CD4+ Th1, Treg and CD8+ T cells and an increase in peripheral neutrophils with overproduction of innate immunity cytokines [64] . These features may be related to differential genetic landscapes, which also include ncRNA genes [64] [65] [66] . Some lncRNAs, such as TSLNC8, MALAT1, NEAT1 and GAS5, have been reported to influence the secretion of IL-6 and the formation of inflammasome platforms, two processes that typically characterize innate immunity [66] . T cell reconstitution during COVID-19 recovery has instead been associated with the lncRNAs CCR7-AS-1, LEF1-AS-1, LINC-CCR7-2, LINC-TCF7-1 and TCF7-AS-1 [64] . Remarkably, none of the above ncRNAs were present in our database. Epigenetic hyperactivation of pathways related to potentiation of the acquired immune response may however lead to long-term transition to established immunemediated diseases, especially in individuals with poor clearance of nucleic acids and defects in apoptosis [67] .

represent an attempt to prevent viral replication. AL139260.2, on the other hand, is normally expressed in testis, heart, and adipose tissue and polymorphic variants have been associated with obesity and dysmetabolism. The upregulation of AL139260.2 in obese and dysmetabolic individuals may be responsible for a more severe course of COVID-19 as reported in several epidemiological studies [68] . The complementary sequence of SARS-CoV-2 may bind AL139260.2 within a promoter site and thus affect the transcription of neighboring genes, such as AL139260.3, MYCBP, RRAGC, which may induce pulmonary fibrosis via a Myc-dependent mechanism [69].

In another RNA-seq study, 21 lncRNAs were found to be up-or downregulated in NHBE cells 24 hours after SARS-CoV-2 infection [21] . Among them, the lncRNA FAM106A, which is also present in our database and has a sequence complementarity to the SARS-CoV-2 ORF6 gene, was significantly hypo-expressed. According to the authors, FAM106A interacts with miRNA let-7c, miRNA let-7f and miRNA-185-5p, which are involved in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT), the Wnt/β-catenin and the mitogen-activated protein kinase (MAPK) pathways. Therefore, it may be hypothesized that SARS-CoV-2 can induce the downregulation of FAM106A via direct nucleotide binding, leading to the overexpression of FAM106A-target miRNAs and eventually to pro-inflammatory and pro-fibrotic events. The potentiation of the Wnt/β-catenin pathway during COVID-19 may also be attributed to the interaction between the SARS-CoV-2 ORF6, ORF7a and ORF10 genes and the lncRNAs MSC-AS1/LINC000689, LINC01606 and MIR100HG, respectively [70] [71] [72] [73] . LncRNAs found in other studies and associated with COVID-19-induced neurological damage or cytokine storm [65, 74] were not present in our database, but these conflicting results might depend on the high tissue-selectivity and time-dependent expression exhibited by these transcripts. For instance, the SARS-CoV-2 gene-matching ncRNAs AC034199.1, COX10-AS1, AC005332.1, AC107068.1, LINC00877, SLFN12L, RNVU1-4, AC100801.1 and LINC00278 retrieved in our analysis show a blood tissue specificity, while pulmonary localization was identified only for the ncRNAs AC110597.1, AC107959.1 and MCM3AP-AS1. As respiratory tissues and leukocytes are the primary targets of infection, these transcripts would play a crucial role in epigenetically controlling the first steps of infection. However, literature data support an alternative SARS-CoV-2 access route via the olfactory tract and thus the central nervous system [75] .

Interestingly, 32 SARS-CoV-2-complementary human lncRNAs listed in our database have a central nervous system-selective expression, and this would be of utmost importance for the epigenetic regulation of viral replication or clearance in this site. However, as shown in other studies [64] , human lncRNA expression in tissue may change longitudinally during the course of infection, thus affecting COVID-19 outcome.

The results of our analysis revealed 13 matches between the SARS-CoV S, N, E, ORF8, ORF6, M and ORF7b genes and human lncRNAs whose polymorphic variants have been associated with a spectrum of immunological diseases [76] [77] [78] . These include IBD [77, 79, 80] , acute Graft-Versus-Host Disease (aGVHD) [81] , systemic lupus erythematosus (SLE) [82] [83] [84] , MS [85] [86] [87] , PsO or atopic dermatitis [76, 77, 88] , systemic sclerosis (SSc) [89, 90] , rheumatoid arthritis (RA) [91] [92] [93] and ankylosing spondylitis (AS) [77, 94] .

However, it cannot be excluded that hyper-expression of SARS-CoV-2-complementary lncRNAs may have a protective role against infection in in patients with full-blown autoimmune diseases. Complementary ncRNAs may act as decoys for viral RNA genomes and compete with them for binding pattern recognition receptors (PRRs) in the cytosol and endosomes. By preventing viral nucleic acid from interacting with sensing platforms, lncRNAs would eventually silence downstream activation of the innate immune response [15] . However, chronic fomentation of this mechanism might have a long-term negative effect on immunosurveillance against pathogens and even transformed cells.

Polymorphisms of CDKN2B-AS1, a lncRNA gene containing an ORF6-complementary sequence, have been associated with MS and type II diabetes mellitus [85, 95] , but evidence suggests that this gene promotes the growth and metastasis of human hepatocellular carcinoma by targeting the microRNA let-7c-5p/NAP1L1 axis [32] . The lncRNA WAKMAR2, which also corresponds to a sequence within the ORF6 gene, has been linked to several immune-mediated disorders in GWAS [76, 84, 85, 88, 89] . This transcript is particularly abundant in the cytosol and nucleus of keratinocytes [33] , where it could be expressed upon stimulation by TGF-β and Smad3 signaling. It has been suggested that WAKMAR2 promotes wound healing and skin re-epithelialization while preventing the expression of chemokines, such as IL-8 and CXCL5, and the activation of the nuclear factor-kB (NF-κB) cascade. Remarkably, TGF- is a key-cytokine in the development of SARS-CoV-2 pulmonary fibrosis [8] and is also associated with carcinogenesis [96] , SSc and interstitial lung disease [97, 98] . The ORF6matching lncRNA LMCD1-AS1 gene, which is associated with SSc risk in Iranian and Turkish populations [90] , is also a certain oncogene for osteosarcoma [99] , cholangiocarcinoma, hepatocellular carcinoma and thyroid cancer [100] . All these data suggest that disruption of this delicate epigenetic balance by SARS-CoV-2 might potentially lead to immune-mediated diseases as well as cancer. Unlike patients with autoimmune diseases [101] , in whom hyper-activity of immune pathways related to the antiviral response might even be useful to counteract the infection, cancer patients usually suffer from a burden of additional comorbidities that expose them to more severe forms of COVID-19 compared to the general population [102] . Furthermore, although J o u r n a l P r e -p r o o f evidence is lacking, the latter may also have impaired clearance of the virus, whose persistence within host cells could epigenetically accelerate cancer progression.

In our analysis, the SARS-CoV-2 ORF6 and ORF10 genes contained sequences showing a Watson-Crick complementarity to two human snRNAs. These are ncRNAs that regulate transcription, splicing and polyadenylation of nascent mRNA transcripts in the nucleus by recruiting specific adaptors such as the Smith (Sm) proteins [103] . Of note, Sm and other small nuclear ribonucleoproteins (snRNPs) contain multiple epitopes recognized by pathognomonic autoantibodies in mixed connective tissue disease (MCTD) and SLE [104, 105] . In this case, SARS-CoV-2 sequence complementarity could disrupt mRNA processing or create new epitopes in snRNPs that could fuel autoimmunity on the ground of a favorable pro-inflammatory background triggered by infection. In this regard, the hyperexpression of RNVU1-4 during COVID-19 recovery coinciding with T-cell response reconstitution [64] should deserve further investigation.

In summary, two scenarios could be depicted based on our findings, Figure 3 . In the first scenario, impaired expression of human ncRNAs might be pre-existent in individuals with certain diseases or disease predispositions and not induced by infection, towards which they may instead play a protective role. In the case of up-regulation, these transcripts could sequester SARS-CoV-2 mRNAs, preventing translation into viral proteins and stimulation of PRRs. This could ultimately lead to either a weakening of the innate immune response or an inhibition of viral replication. Although some studies show the opposite [106] , it may be hypothesized that this mechanism functions as a kind of "genetic immune system" that blocks the initial steps of viral infections. In support of this view, we found that polymorphisms of most of the detected ncRNA genes were associated with neurodegenerative and neuropsychiatric diseases and there is evidence that approximately 40% of lncRNAs are expressed in the mammalian brain during neurogenesis and neuronal differentiation [34] .

Consequently, humans with neurological diseases may have impaired expression of these ncRNAs, with unfavorable repercussions on SARS-CoV-2 infection. In line with this hypothesis, a recent UK Biobank study found an increased risk of complicated COVID-19 in Alzheimer's disease patients [107] .

In the second scenario, SARS-CoV-2 infection would be the starting point for aberrant expression of ncRNAs in human cells, which could lead to long-term health complications. SARS-CoV-2 nucleic acids could enhance or repress the transcription of ncRNAs by binding the corresponding nucleotide sequences on the human genome.

We found that SARS-CoV-2 gene complementarities lie within 31 regulatory sites whose neighboring coding genes may be involved in oncological, immunological, neurological, cardiovascular, pulmonary, metabolic, and musculoskeletal diseases. In addition, our results show that SARS-CoV-2 sequences may disrupt interactions J o u r n a l P r e -p r o o f between lncRNAs transcripts and transcription factors or other regulatory RNA-and DNA-binding proteins, potentially leading to abnormal activation of downstream signaling pathways associated with cancer and autoimmunity. Finally, interaction with snRNAs may contribute to the formation of self-epitopes within the RNP complex, increasing the risk of autoimmune diseases. These nuclear effects presuppose that SARS-CoV-2 RNA may cross the nuclear membrane and localize in the nucleus. Interestingly, a recent paper based on computational analysis reported that SARS-CoV-2 RNA may have a subcellular residency within the nucleolus or mitochondrial matrix of host cells [108] . The authors found that among all ORF3a, S, ORF7b, ORF8, ORF6

and ORF7a showed the strongest residency signal towards the nucleolus. Trafficking of the SARS-CoV-2 RNA, either as a positive or negative strand, within the nucleus could explain a plausible interaction with the human lncRNAs MEG8, FAM30A and MIR100HG, which show a nuclear localization and, according to our analysis, correspond to ORF6, ORF7a and ORF10 sequences, respectively. Further confirmation comes from an in vitro study by Zhang et al. showing that SARS-CoV-2 RNA could be retrotranscribed and integrated into the human genome [109] . This event would occur mainly in individuals with enhanced activity of Long Interspersed Nuclear Elements-1 (LINEs-1) and telomerase, which may be induced by the infection itself or by chronic cytokine stimulation or other signaling pathways occurring in cancer or autoimmune diseases [110, 111] .

A major limitation of this study lies in the in silico design that prevents from extensively investigating the dynamic expression and interactions between SARS-CoV-2 genes and host ncRNAs during disease progression.

Further in vitro or ex-vivo studies are needed to explore how host SARS-CoV-2-complementary lncRNAs change after virus invasion and subsequently affect virus replication.

This in silico study suggests the possibility of Watson-Crick complementarity between SARS-CoV-2 RNA and human ncRNAs, including lncRNAs and snRNAs. The matches may involve either chromatin regulatory sequences or RNA protein-binding sites, thus affecting the transcription of multiple genes involved in human diseases. Although the possibility of direct base-pairing between viral RNA and host ncRNA remains to be further confirmed in vitro, it seems plausible that SARS-CoV-2 infection could lead to aberrant virus-host nucleic acid crosstalk with long-term implications for human health. Polymorphic variants of the retrieved ncRNAs could be associated with different COVID-19 outcomes (e.g., severe forms versus asymptomatic cases) and long-term complications and therefore represent potential biomarkers for identifying individuals at higher risk of severe disease. Immunol. 10 (2019) Human health condition, disease Human noncoding RNA Complementary SARS-CoV-2 gene Anthropometric indices (height, weight, body mass index, body fat mass, fat-free mass, waist-hip ratio, obesity, visceral adipose tissue measurement, subcutaneous adipose tissue measurement, waist circumference, fat distribution, hip circumference adjusted for body mass index, waist circumference adjusted for body mass index)

Cardiovascular diseases (arrhythmia, arterial stiffness measurement, congenital heart diseases, systolic and diastolic blood pressure, coronary artery calcification and disease, aortic root size, artery dissection and aneurysm, venous thromboembolism, heart failure, stroke, carotid atherosclerosis, myocardial infarction, mitral valve prolapse)

ORF10 Cancer (breast, thyroid, colorectum, melanoma and non-melanoma skin cancer, glioma and glioblastoma, hepatocellular and renal cancer, nasopharyngeal carcinoma, endometrial and prostate cancer, oesophageal squamous cell cancer and adenocarcinoma, oral cavity cancer, acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma, epithelial ovarian cancer, squamous cell lung cancer and lung adenocarcinoma, testicular germ cell tumour, gallbladder and cervical cancer, neuroblastoma, pancreatic cancer)

ORF7b -MIR100HG ORF10 Immune-mediated disorders (inflammatory bowel diseases, acute graft-versus-host disease, systemic lupus erythematosus, multiple sclerosis, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, systemic sclerosis, sarcoidosis, autoimmune thyroiditis, sclerosing cholangitis, celiac disease, type 1 diabetes mellitus, juvenile idiopathic arthritis, Takayasu arteritis, IgA deficit, atopy)

Pulmonary diseases and impairment in pulmonary function tests (FEV1, FVC, post bronchodilator FEV1/FVC ratio, asthma, forced expiratory volume, response to bronchodilator, vital capacity, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, obstructive sleep apnoea during REM sleep, emphysema)

ORF10 Susceptibility/response to infections (Tripanosoma cruzi, tuberculosis, mumps, rubella, leprosy, severe malaria, scarlet fever, measles, HIV, HCV, H1N1 virus, sepsis)

ORF7a Neuropsychiatric disorders (Alzheimer disease and age of onset, general cognitive ability, memory performance, brain volume, mathematical ability, intelligence, cerebral

J o u r n a l P r e -p r o o f cortical surface area measurement, schizophrenia, autism, generalised epilepsy, anorexia nervosa, attentiondeficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, unipolar depression, functional impairment measurement, periventricular white matter hyperintensities and white matter microstructure, PHF-tau measurement, insomnia, Parkinson's disease, education and temperament, spinal muscular atrophy type 1; childhood muscular atrophy, migraine without aura, neurofibrillary tangles, amyotrophic lateral sclerosis, caudal middle frontal gyrus volume, narcolepsy, suicide attempts in bipolar disorder or schizophrenia, sleep pattern and duration, sphingomyelin measurement, Tourette syndrome, risk-taking behaviour, brain connectivity, social communication impairment)

ORF10 Dysmetabolism (type 1 and 2 diabetes mellitus, dyslipidemia, uric acid serum levels, leptin serum levels)

ORF7b Hematopoietic cell disorders (red and white blood cell count, hematocrit, neutrophil/lymphocyte ratio, platelet count and aggregation, mean corpuscular volume, reticulocyte count, red blood cell distribution width)

ORF10 Renal diseases (estimated glomerular filtration rate, diabetic nephropathy, renal insufficiency)

ORF7b Bone disorders (heel and hip bone mineral density)

ORF10 Reproductive disorders (sex hormone serum levels, fertility, endometriosis)

ORF7a Gastrointestinal diseases (dysgeusia, hepatitis, pancreatitis, Barrett's oesophagus, dysphagia, velopharyngeal dysfunction, gut microbiota composition)

ORF10 Abbreviations: FEV1, forced expiratory volume in the 1st second; FVC, forced vital capacity; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PHF, paired helical filaments; REM, rapid eye movement. In the first scenario (a), ncRNAs are pre-existent and hyper-expressed in a cell undergoing SARS-CoV-2

infection. Due to sequence complementarity to SARS-CoV-2 RNA, these transcripts may intercept the viral genome in the cytosol and prevent translation into functional proteins and interaction with PRRs. In addition, they may compete with viral RNA for PRRs and thus mediate a downstream inhibitory signal on the activation of the immune response.

In the second scenario (b), SARS-CoV-2 infection may alter the expression of ncRNAs. Taking advantage by its sequence complementarity, SARS-CoV-2 RNA may interfere with the binding of transcription factors and other proteins to regulatory sites of lncRNA genes, thereby indirectly affecting the transcription of adjacent genes.

This would lead to a profound alteration of the epigenetic landscape that eventually translates into uncontrolled proliferation pathways. Furthermore, binding of the SARS-CoV-2 genome to complementary snRNA sequences may generate novel epitopes within the RNP complex that fuel autoimmunity.

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Table 1. List of the human ncRNAs (gene and transcripts) displaying a nucleotide sequence complementarity to NISCH LINC02354, AC095060.1, DIRC3, MYO3B-AS1, AC009107.2, AL139260.2, ZNRF3-AS1, AC034199.1, AC092447.5, AC104574.2, CCNT2-AS1, LINC01358, INE2, AC092162.2, AC005332.1, AC107068.1, LINC00877, MCM3AP-AS1, CDKN2B-AS1, MSC-AS1

J o u r n a l P r e -p r o o f