m6A Regulator-Mediated Methylation Modification Patterns and Characteristics of Immunity in Blood Leukocytes of COVID-19 Patients

Qiu, Xiangmin; Hua, Xiaoliang; Li, Qianyin; Zhou, Qin; Chen, Juan

doi:10.3389/fimmu.2021.774776

Cited by 18 publications

(23 citation statements)

References 53 publications

(106 reference statements)

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“…Since the YTH-domain family 2 (YTHDF2) protein mediates the deadenylation that decays m 6 A-marked transcripts [803,804], replication of the SARS-CoV-2 virus is deemed to be sensitive to the negative regulation by m 6 A "reader" YTHDF2 [802]. An analysis of RNA-seq of 126 COVID-19 patient blood samples from a GEO dataset revealed a strikingly elevated level of m 6 A modification associated with increased expression of CD4 + T cells in leukocytes of infected compared to uninfected individuals [805]. A systematic analysis of RNA-seq and clinical data obtained from 100 COVID-19 and 26 non-COVID-19 subjects revealed that the expression of both METTL3 "writers" and FTO "erasers" were increased in the 100 COVID-19 patients but not in non-COVID-19 controls, where m 6 A targeted genes were differentially expressed.…”

Section: Is M 6 a A Positive Or Negative Regulator Of Sars-cov-2 Repl...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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Section: Is M 6 a A Positive Or Negative Regulator Of Sars-cov-2 Repl...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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“…In addition, we found no correlation between viral load and m6A levels across variants. However, previous studies have reported a higher m6A level in lung or peripheral blood from patients with moderate or severe COVID-19 disease compared to healthy individuals [ 13 , 17 , 18 , 26 ]. Interestingly, in peripheral blood these changes were associated with increased expression of RBM15 [ 17 ].…”

Section: Discussionmentioning

confidence: 96%

“…Interestingly, in peripheral blood these changes were associated with increased expression of RBM15 [ 17 ]. Moreover, Qiu et al [ 26 ] proposed a predictive “m6A score” to quantify and model the m6A pattern in blood leukocytes for each COVID-19 patient based on m6A levels and nine selected differentially expressed genes (m6A-DEGs) mostly related to the immune response; in this model, patients displaying higher (protective) scores showed a better prognosis related to T-cell activation compared to patients with lower scores; in addition to clinical prognosis, the model may predict the possibility of contracting COVID-19 in patients infected with SARS-CoV-2, as well as the detection of SARS-CoV-2 carriers [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Global m6A RNA Methylation in SARS-CoV-2 Positive Nasopharyngeal Samples in a Mexican Population: A First Approximation Study

et al. 2022

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The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the causal agent of COVID-19 (Coronavirus Disease-19). Both mutation and/or recombination events in the SARS-CoV-2 genome have resulted in variants that differ in transmissibility and severity. Furthermore, RNA methylation of the N6 position of adenosine (m6A) is known to be altered in cells infected with SARS-CoV-2. However, it is not known whether this epitranscriptomic modification differs across individuals dependent on the presence of infection with distinct SARS-CoV-2 variants, the viral load, or the vaccination status. To address this issue, we selected RNAs (n = 60) from SARS-CoV-2 sequenced nasopharyngeal samples (n = 404) of 30- to 60-year-old outpatients or hospitalized individuals from the city of Mazatlán (Mexico) between February 2021 and March 2022. Control samples were non-infected individuals (n = 10). SARS-CoV-2 was determined with real-time PCR, viral variants were determined with sequencing, and global m6A levels were determined by using a competitive immunoassay method. We identified variants of concern (VOC; alpha, gamma, delta, omicron), the variant of interest (VOI; epsilon), and the lineage B.1.1.519. Global m6A methylation differed significantly across viral variants (p = 3.2 × 10−7). In particular, we found that m6A levels were significantly lower in the VOC delta- and omicron-positive individuals compared to non-infected individuals (p = 2.541236 × 10−2 and 1.134411 × 10−4, respectively). However, we uncovered no significant correlation between global m6A levels and viral nucleocapsid (N) gene expression or age. Furthermore, individuals with complete vaccination schemes showed significantly lower m6A levels than unvaccinated individuals (p = 2.6 × 10−4), and differences in methylation levels across variants in unvaccinated individuals were significant (p = 3.068 × 10−3). These preliminary results suggest that SARS-CoV-2 variants show differences in global m6A levels.

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“…Currently, the relationship between m 6 A and gut microbiota in cancer development has not been explored. It is reported that virus infection, such as rotavirus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), induces global m 6 A modifications on mRNA transcripts of host cells and affects host immune defense against virus infections [ 106 – 109 ]. Therefore, a better understating of the potential functional interaction of gut microbes with the host m 6 A machinery may offer new strategies for the development of innovative therapies against cancer.…”

Section: The Potential Role Of the M 6 A Modificat...mentioning

confidence: 99%

Targeting the RNA m6A modification for cancer immunotherapy

et al. 2022

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N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

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m6A Regulator-Mediated Methylation Modification Patterns and Characteristics of Immunity in Blood Leukocytes of COVID-19 Patients

Cited by 18 publications

References 53 publications

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Global m6A RNA Methylation in SARS-CoV-2 Positive Nasopharyngeal Samples in a Mexican Population: A First Approximation Study

Targeting the RNA m6A modification for cancer immunotherapy

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