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Open accessJournal ArticleDOI: 10.1080/15592294.2020.1796896

Epigenetic mechanisms regulating COVID-19 infection.

04 Mar 2021-Epigenetics (Taylor & Francis)-Vol. 16, Iss: 3, pp 263-270
Abstract: Coronavirus disease 2019 (COVID-2019) outbreak originating in December 2019 in Wuhan, China has emerged as a global threat to human health. The highly contagious SARS-CoV-2 infection and transmission presents a diversity of human host and increased disease risk with advancing age, highlighting the importance of in-depth understanding of its biological properties. Structural analyses have elucidated hot spots in viral binding domains, mutations, and specific proteins in the host such as the receptor angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine 2 (TMPRSS2) to be implicated in cell entry and viral infectivity. Furthermore, epigenetic changes that regulate chromatin structure have shown a major impact in genome stabilization and maintenance of cellular homoeostasis and they have been implicated in the pathophysiology of the virus infection. Epigenetic research has revealed that global DNA methylation along with ACE2 gene methylation and post-translational histone modifications may drive differences in host tissue-, biological age- and sex-biased patterns of viral infection. Moreover, modulation of the host cells epigenetic landscape following infection represents a molecular tool used by viruses to antagonize cellular signalling as well as sensing components that regulate the induction of the host innate immune and antiviral defence programmes in order to enhance viral replication and infection efficiency. In this review, we provide an update of the main research findings at the interface of epigenetics and coronavirus infection. In particular, we highlight the epigenetic factors that interfere with viral replication and infection and may contribute to COVID-19 susceptibility, offering new ways of thinking in respect to host viral response.

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Topics: Epigenetics (55%), Viral replication (54%), DNA methylation (51%) ... read more
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Open accessJournal ArticleDOI: 10.1002/JGM.3303
Abstract: BACKGROUND: At the end of December 2019, a novel coronavirus tentatively named SARS-CoV-2 in Wuhan, a central city in China, was announced by the World Health Organization (WHO). SARS-CoV-2 is an RNA virus that has become a major public health concern after the outbreak of the Middle East Respiratory Syndrome-CoV (MERS-CoV) and Severe Acute Respiratory Syndrome-CoV (SARS-CoV) in 2002 and 2012, respectively. As of October 29, 2020, the total number of COVID-19 cases had reached over 44 million worldwide, with more than 1.17 million confirmed deaths. DISCUSSION: SARS-CoV-2 infected patients usually present with severe viral pneumonia. Similar to SARS-CoV, the virus enters respiratory tract cells via the angiotensin-converting enzyme receptor 2. The structural proteins play an essential role in budding the virus particles released from different host cells. To date, an approved vaccine or treatment option of a preventive character to avoid severe courses of COVID-19 is still not available. CONCLUSION: In this study, we provide a brief review of the general biological features of CoVs and explain the pathogenesis, clinical symptoms, and diagnostic approaches regarding monitoring future infectivity and prevent emerging COVID-19 infections.

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Topics: Coronavirus (55%), Viral pneumonia (54%)

29 Citations


Open accessJournal ArticleDOI: 10.3390/V12121433
13 Dec 2020-Viruses
Abstract: Innate immune interferons (IFNs), including type I and III IFNs, constitute critical antiviral mechanisms. Recent studies reveal that IFN dysregulation is key to determine COVID-19 pathogenesis. Effective IFN stimulation or prophylactic administration of IFNs at the early stage prior to severe COVID-19 may elicit an autonomous antiviral state, restrict the virus infection, and prevent COVID-19 progression. Inborn genetic flaws and autoreactive antibodies that block IFN response have been significantly associated with about 14% of patients with life-threatening COVID-19 pneumonia. In most severe COVID-19 patients without genetic errors in IFN-relevant gene loci, IFN dysregulation is progressively worsened and associated with the situation of pro-inflammation and immunopathy, which is prone to autoimmunity. In addition, the high correlation of severe COVID-19 with seniority, males, and individuals with pre-existing comorbidities will be plausibly explained by the coincidence of IFN aberrance in these situations. Collectively, current studies call for a better understanding of the IFN response regarding the spatiotemporal determination and subtype-specificity against SARS-CoV-2 infections, which are warranted to devise IFN-related prophylactics and therapies.

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25 Citations


Open accessJournal ArticleDOI: 10.1186/S13148-020-00946-X
Abstract: Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19.

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Topics: Coronavirus (60%), Epigenome (58%), Epigenetics (57%) ... read more

20 Citations


Open accessJournal ArticleDOI: 10.3390/VACCINES8040700
20 Nov 2020-Vaccine
Abstract: SARS-CoV2 has caused the current pandemic of new coronavirus disease 2019 (COVID-19) worldwide. Clinical outcomes of COVID-19 illness range broadly from asymptotic and mild to a life-threatening situation. This casts uncertainties for defining host determinants underlying the disease severity. Recent genetic analyses based on extensive clinical sample cohorts using genome-wide association studies (GWAS) and high throughput sequencing curation revealed genetic errors and gene loci associated with about 20% of life-threatening COVID-19 cases. Significantly, most of these critical genetic loci are enriched in two immune signaling pathways, i.e., interferon-mediated antiviral signaling and chemokine-mediated/inflammatory signaling. In line with these genetic profiling studies, the broad spectrum of COVID-19 illness could be explained by immuno-pathological regulation of these critical immunogenetic pathways through various epigenetic mechanisms, which further interconnect to other vital components such as those in the renin-angiotensin-aldosterone system (RAAS) because of its direct interaction with the virus causing COVID-19. Together, key genes unraveled by genetic profiling may provide targets for precisely early risk diagnosis and prophylactic design to relieve severe COVID-19. The confounding epigenetic mechanisms may be key to understanding the clinical broadness of COVID-19 illness.

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18 Citations


Journal ArticleDOI: 10.1139/GEN-2020-0124
01 Apr 2021-Genome
Abstract: The angiotensin-converting enzyme 2 (ACE2) is the receptor for the three coronaviruses HCoV-NL63, SARS-CoV, and SARS-CoV-2. ACE2 is involved in the regulation of the renin-angiotensin system and blood pressure. ACE2 is also involved in the regulation of several signaling pathways, including integrin signaling. ACE2 expression is regulated transcriptionally and post-transcriptionally. The expression of the gene is regulated by two promoters, with usage varying among tissues. ACE2 expression is greatest in the small intestine, kidney, and heart and detectable in a variety of tissues and cell types. Herein we review the chemical and mechanical signal transduction pathways regulating the expression of the ACE2 gene and the epigenetic/chromatin features of the expressed gene.

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Topics: Regulation of gene expression (63%), Signal transduction (56%), Chromatin (55%) ... read more

13 Citations


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37 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2020.02.052
16 Apr 2020-Cell
Abstract: The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Topics: Proteases (52%)

10,193 Citations


Journal ArticleDOI: 10.1038/38444
18 Sep 1997-Nature
Abstract: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.

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Topics: Histone octamer (75%), Histone fold (74%), Histone binding (71%) ... read more

7,215 Citations


Open accessJournal ArticleDOI: 10.1038/CR.2011.22
Andrew J. Bannister1, Tony Kouzarides1Institutions (1)
15 Feb 2011-Cell Research
Abstract: Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

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Topics: Histone code (74%), Epigenomics (65%), Histone-modifying enzymes (65%) ... read more

3,710 Citations


Open accessJournal ArticleDOI: 10.1128/JVI.00127-20
Yushun Wan1, Jian Shang1, Rachel L. Graham2, Ralph S. Baric2  +1 moreInstitutions (2)
Abstract: Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV.IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.

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Topics: Coronavirus (55%)

2,755 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.51.5.786
Abstract: 17 Ohno, S., and B. M. Cattanach, Cytogenet., 1, 129 (1962). 18 Russell, L. B., Science, 140, 976 (1963). 19 Lyon, M. F., Genetic Res., 4, 93 (1963). *' Benirschke, K., R. J. Low, L. E. Brownhill, L. B. Caday, and J. deVenecia-Fernandez, Chromosoma, in press. 21 Davidson, R. G., H. M. Nitowsky, and B. Childs, these PROCEEDINGS, 50, 481 (1963). 22Beutler, E., and M. Baluda, Lancet, I, 189 (1964). 23 Bach, F., and K. Hirschhorn, Proc. 11th Intern. Congr. Genet., p. 312 (1963). 24Sanger, R., R. R. Race, P. Tippett, J. Hamper, J. Gavin, and T. E. Cleghorn, Vox Sang., 7, 571 (1962) 2 Gorman, J. G., A. M. Treacy, and A. Cahan, J. Lab. Clin. Med., 61, 642 (1963). 26Reed, T. E., N. E. Simpson, and B. Chown, Lancet, H, 467 (1963). 27 Lindsten, J., M. Fraccaro, P. E. Polani, J. L. Hamerton, R. Sanger, and R. R. Race, Nature, 197, 648 (1963). '\" Muldal, S., L. Tiepolo, M. Fraccaro, and J. Lindsten, unpublished data.

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Topics: Histone methylation (60%), Histone (59%), RNA (56%) ... read more

2,162 Citations