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1.
Transl Psychiatry ; 12(1): 386, 2022 09 16.
Article in English | MEDLINE | ID: covidwho-2036783

ABSTRACT

Stress exposure during pregnancy is critically linked with maternal mental health and child development. The effects might involve altered patterns of DNA methylation in specific stress-related genes (i.e., glucocorticoid receptor gene, NR3C1, and serotonin transporter gene, SLC6A4) and might be moderated by the gestational timing of stress exposure. In this study, we report on NR3C1 and SLC6A4 methylation status in Italian mothers and infants who were exposed to the COVID-19 pandemic lockdown during different trimesters of pregnancy. From May 2020 to February 2021, 283 mother-infant dyads were enrolled at delivery. Within 24 h from delivery, buccal cells were collected to assess NR3C1 (44 CpG sites) and SLC6A4 (13 CpG sites) methylation status. Principal component (PC) analyses were used to reduce methylation data dimension to one PC per maternal and infant gene methylation. Mother-infant dyads were split into three groups based on the pregnancy trimester (first, second, third), during which they were exposed to the COVID-19 lockdown. Mothers and infants who were exposed to the lockdown during the first trimester of pregnancy had lower NR3C1 and SLC6A4 methylation when compared to counterparts exposed during the second or third trimesters. The effect remained significant after controlling for confounders. Women who were pregnant during the pandemic and their infants might present altered epigenetic biomarkers of stress-related genes. As these epigenetic marks have been previously linked with a heightened risk of maternal psychiatric problems and less-than-optimal child development, mothers and infants should be adequately monitored for psychological health during and after the pandemic.


Subject(s)
COVID-19 , Epigenesis, Genetic , Quarantine , Receptors, Glucocorticoid , Serotonin Plasma Membrane Transport Proteins , COVID-19/epidemiology , COVID-19/prevention & control , Child , Communicable Disease Control , Epigenesis, Genetic/genetics , Female , Humans , Infant , Mouth Mucosa/metabolism , Pandemics/prevention & control , Pregnancy , Quarantine/psychology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism
2.
Genes (Basel) ; 13(7)2022 06 21.
Article in English | MEDLINE | ID: covidwho-1963781

ABSTRACT

Single-cell transcriptome studies have revealed immune dysfunction in COVID-19 patients, including lymphopenia, T cell exhaustion, and increased levels of pro-inflammatory cytokines, while DNA methylation plays an important role in the regulation of immune response and inflammatory response. The specific cell types of immune responses regulated by DNA methylation in COVID-19 patients will be better understood by exploring the COVID-19 DNA methylation variation at the cell-type level. Here, we developed an analytical pipeline to explore single-cell DNA methylation variations in COVID-19 patients by transferring bulk-tissue-level knowledge to the single-cell level. We discovered that the methylation variations in the whole blood of COVID-19 patients showed significant cell-type specificity with remarkable enrichment in gamma-delta T cells and presented a phenomenon of hypermethylation and low expression. Furthermore, we identified five genes whose methylation variations were associated with several cell types. Among them, S100A9, AHNAK, and CX3CR1 have been reported as potential COVID-19 biomarkers previously, and the others (TRAF3IP3 and LFNG) are closely associated with the immune and virus-related signaling pathways. We propose that they might serve as potential epigenetic biomarkers for COVID-19 and could play roles in important biological processes such as the immune response and antiviral activity.


Subject(s)
COVID-19 , DNA Methylation , Biomarkers , COVID-19/genetics , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Glycosyltransferases/genetics , Humans , Single-Cell Analysis
3.
Bioessays ; 44(2): e2100239, 2022 02.
Article in English | MEDLINE | ID: covidwho-1606656

ABSTRACT

Throughout evolution, there has been interaction and exchange between RNA pools in the environment, and DNA and RNA pools of eukaryotic organisms. Metagenomic and metatranscriptomic sequencing of invertebrate hosts and their microbiota has revealed a rich evolutionary history of RNA virus shuttling between species. Horizontal transfer adapted the RNA pool for successful future interactions which lead to zoonotic transmission and detrimental RNA viral pandemics like SARS-CoV2. In eukaryotes, noncoding RNA (ncRNA) is an established mechanism derived from prokaryotes to defend against viral attack through innate immunity and regulation of host-derived mRNA. Transgenerational inheritance of ncRNA is evidence for feedforward adaptive immunity and epigenetically encoded environmental change across generations, which may explain the ''missing heritability'' of common disease. Causal graph theory and the Price Equation can model epigenetic inheritance involving dynamic internal and external RNA pools. Experimental designs should include metatranscriptomic analyses to understand how ncRNA responds to rapidly changing environmental conditions, within and between organisms, and across generations.


Subject(s)
COVID-19 , Epigenesis, Genetic , DNA , Epigenesis, Genetic/genetics , Humans , RNA, Viral , Repetitive Sequences, Nucleic Acid , SARS-CoV-2
4.
Clin Epigenetics ; 13(1): 187, 2021 10 11.
Article in English | MEDLINE | ID: covidwho-1526657

ABSTRACT

BACKGROUND: SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements. RESULTS: We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA. CONCLUSIONS: Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/prevention & control , Epigenesis, Genetic/physiology , Neuropilin-1/genetics , Receptors, Virus/drug effects , Valproic Acid/pharmacology , Angiotensin-Converting Enzyme 2/drug effects , Antiviral Agents/pharmacology , Cells, Cultured , Enzyme Inhibitors/pharmacology , Epigenesis, Genetic/genetics , Humans , Neuropilin-1/drug effects , SARS-CoV-2
5.
Eur Rev Med Pharmacol Sci ; 25(19): 5947-5964, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1478937

ABSTRACT

The recent Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) outbreak has resulted in coronavirus disease 2019 (COVID-19) pandemic worldwide, affecting millions of lives. Although vaccines are presently made available, and vaccination drive is in progress to immunize a larger population; still the risk of SARS-CoV-2 infection and related mortality is persistent amid threats of the third wave of the ongoing pandemic. In the scenario of unavailability of robust and efficient treatment modalities, it becomes essential to understand the mechanism of action of the virus and deeply study the molecular mechanisms (both at the virus level and the host level) underlying the infection processes. Recent studies have shown that coronaviruses (CoVs) cause-specific epigenetic changes in the host cells to create a conducive microenvironment for replicating, assembling, and spreading. Epigenetic mechanisms can contribute to various aspects of the SARS-CoV-2 multiplication cycle, like expressing cytokine genes, viral receptor ACE2, and implicating different histone modifications. For SARS-CoV-2 infection, viral proteins are physically associated with various host proteins resulting in numerous interactions between epigenetic enzymes (i.e., histone deacetylases, bromodomain-containing proteins). The involvement of epigenetic mechanisms in the virus life cycle and the host immune responses to control infection result in epigenetic factors recognized as emerging prognostic COVID-19 biomarkers and epigenetic modulators as robust therapeutic targets to curb COVID-19. Therefore, this narrative review aimed to summarize and discuss the various epigenetic mechanisms that control gene expression and how these mechanisms are altered in the host cells during coronavirus infection. We also discuss the opportunities to exploit these epigenetic changes as therapeutic targets for SARS-CoV-2 infection. Epigenetic alterations and regulation play a pivotal role at various levels of coronavirus infection: entry, replication/transcription, and the process of maturation of viral proteins. Coronaviruses modulate the host epigenome to escape the host immune mechanisms. Therefore, host epigenetic alterations induced by CoVs can be considered to develop targeted therapies for COVID-19.


Subject(s)
COVID-19/genetics , COVID-19/therapy , Coronavirus Infections/genetics , Coronavirus Infections/therapy , Epigenesis, Genetic/genetics , Epigenome , Host-Pathogen Interactions , Humans
7.
Eur J Immunol ; 51(7): 1641-1651, 2021 07.
Article in English | MEDLINE | ID: covidwho-1473829

ABSTRACT

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators - chromatin remodeling and histone modification - in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.


Subject(s)
Antiviral Agents/immunology , Epigenesis, Genetic/genetics , Epigenesis, Genetic/immunology , Immunity, Innate/genetics , Immunity, Innate/immunology , Animals , Chromatin/genetics , Chromatin/immunology , Histones/genetics , Histones/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , RNA Processing, Post-Transcriptional/genetics , RNA Processing, Post-Transcriptional/immunology
8.
Ann Hum Genet ; 85(6): 221-234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1286650

ABSTRACT

In the early 2000s, emerging SARS-CoV-2, which is highly pathogenic, posed a great threat to public health. During COVID-19, epigenetic regulation is deemed to be an important part of the pathophysiology and illness severity. Using the Illumina Infinium Methylation EPIC BeadChip (850 K), we investigated genome-wide differences in DNA methylation between healthy subjects and COVID-19 patients with different disease severities. We conducted a combined analysis and selected 35 "marker" genes that could indicate a SARS-CoV-2 infection, including 12 (ATHL1, CHN2, CHST15, CPLX2, CRHR2, DCAKD, GNAI2, HECW1, HYAL1, MIR510, PDE11A, and SMG6) situated in the promoter region. The functions and pathways of differentially methylated genes were enriched in biological processes, signal transduction, and the immune system. In the "Severe versus Mild" group, differentially methylated genes, after eliminating duplicates, were used for PPI analyses. The four hub genes (GNG7, GNAS, PRKCZ, and PRKAG2) that had the highest degree of nodes were identified and among them, GNG7 and GNAS genes expressions were also downregulated in the severe group in sequencing results. Above all, the results suggest that GNG7 and GNAS may play a non-ignorable role in the progression of COVID-19. In conclusion, the identified key genes and related pathways in the current study can be used to study the molecular mechanisms of COVID-19 and may provide possibilities for specific treatments.


Subject(s)
COVID-19/genetics , COVID-19/pathology , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Severity of Illness Index , Adult , Chromogranins/genetics , CpG Islands/genetics , Epigenome/genetics , Female , GTP-Binding Protein alpha Subunits, Gs/genetics , GTP-Binding Protein gamma Subunits/genetics , Genetic Markers/genetics , Humans , Inflammation/pathology , Male , Middle Aged , SARS-CoV-2
10.
NPJ Syst Biol Appl ; 7(1): 21, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1241950

ABSTRACT

COVID-19 is an infection caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), which has caused a global outbreak. Current research efforts are focused on the understanding of the molecular mechanisms involved in SARS-CoV-2 infection in order to propose drug-based therapeutic options. Transcriptional changes due to epigenetic regulation are key host cell responses to viral infection and have been studied in SARS-CoV and MERS-CoV; however, such changes are not fully described for SARS-CoV-2. In this study, we analyzed multiple transcriptomes obtained from cell lines infected with MERS-CoV, SARS-CoV, and SARS-CoV-2, and from COVID-19 patient-derived samples. Using integrative analyses of gene co-expression networks and de-novo pathway enrichment, we characterize different gene modules and protein pathways enriched with Transcription Factors or Epifactors relevant for SARS-CoV-2 infection. We identified EP300, MOV10, RELA, and TRIM25 as top candidates, and more than 60 additional proteins involved in the epigenetic response during viral infection that has therapeutic potential. Our results show that targeting the epigenetic machinery could be a feasible alternative to treat COVID-19.


Subject(s)
COVID-19/genetics , Epigenesis, Genetic/genetics , SARS-CoV-2/genetics , Transcriptome/genetics , COVID-19/virology , Gene Expression Profiling , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/genetics , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Signal Transduction/genetics
11.
Pharmacogenomics ; 21(18): 1311-1329, 2020 12.
Article in English | MEDLINE | ID: covidwho-948025

ABSTRACT

There is considerable variation in disease course among individuals infected with SARS-CoV-2. Many of them do not exhibit any symptoms, while some others proceed to develop COVID-19; however, severity of COVID-19 symptoms greatly differs among individuals. Focusing on the early events related to SARS-CoV-2 entry to cells through the ACE2 pathway, we describe how variability in (epi)genetic factors can conceivably explain variability in disease course. We specifically focus on variations in ACE2, TMPRSS2 and FURIN genes, as central components for SARS-CoV-2 infection, and on other molecules that modulate their expression such as CALM, ADAM-17, AR and ESRs. We propose a genetic classifier for predicting SARS-CoV-2 infectivity potential as a preliminary tool for identifying the at-risk-population. This tool can serve as a dynamic scaffold being updated and adapted to validated (epi)genetic data. Overall, the proposed approach holds potential for better personalization of COVID-19 handling.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Furin/genetics , Serine Endopeptidases/genetics , ADAM17 Protein/genetics , COVID-19/epidemiology , COVID-19/virology , Epigenesis, Genetic/genetics , Humans , Monomeric Clathrin Assembly Proteins/genetics , Prognosis , Receptors, Androgen/genetics , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
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