Melatonin restores the pluripotency of long‐term‐cultured embryonic stem cells through melatonin receptor‐dependent m6A RNA regulation

Yang, Lei; Liu, Xuefei; Song, Lishuang; Su, Guanghua; Di, Anqi; Bai, Chunling; Wei, Zhuying; Li, Guangpeng

doi:10.1111/jpi.12669

Cited by 30 publications

(31 citation statements)

References 64 publications

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“…For example, KLF4 negatively regulated cellular antiviral response by inhibiting the activation of NF-κB by TNF-α and IL-1β ( 19 ). In addition, melatonin was found to stabilize KLF4 by preventing its m 6 A-dependent mRNA decay ( 20 ). However, whether and how KLF4 is regulated by the N 6-methyladenosine (m 6 A) modification via virus–host interaction need to be further elucidated.…”

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confidence: 99%

Identification of an N6-methyladenosine-mediated positive feedback loop that promotes Epstein–Barr virus infection

Dai

Wang

et al. 2021

Journal of Biological Chemistry

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N6-methyladenosine (m 6 A) is among the most abundant mRNA modifications, particularly in eukaryotes, and is found in mammals, plants, and even some viruses. Although essential for the regulation of many biological processes, the exact role of m 6 A modification in virus–host interaction remains largely unknown. Here, using m 6 A -immunoprecipitation and sequencing, we find that Epstein–Barr virus (EBV) infection decreases the m 6 A modification of transcriptional factor KLF4 mRNA and subsequently increases its protein level. Mechanistically, EBV immediate-early protein BZLF1 interacts with the promoter of m 6 A methyltransferase METTL3, inhibiting its expression. Subsequently, the decrease of METTL3 reduces the level of KLF4 mRNA m 6 A modification, preventing its decay by the m 6 A reader protein YTHDF2. As a result, KLF4 protein level is upregulated and, in turn, promotes EBV infection of nasopharyngeal epithelial cells. Thus, our results suggest the existence of a positive feedback loop formed between EBV and host molecules via cellular mRNA m 6 A levels, and this feedback loop acts to facilitate viral infection. This mechanism contains multiple potential targets for controlling viral infectious diseases.

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confidence: 99%

Identification of an N6-methyladenosine-mediated positive feedback loop that promotes Epstein–Barr virus infection

Dai

Wang

et al. 2021

Journal of Biological Chemistry

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“…Numerous studies in recent years have shown that N6methyladenosine (m6A) methylation is a commonly seen modification in eukaryotic messenger RNA (mRNA) and strongly affects many basic biological processes, such as cell differentiation, tissue development and tumorigenesis (9)(10)(11)(12). The level of m6A methylation is regulated by methyltransferases, demethylases, and binding proteins.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of PD-L1 Expression, Immune Infiltrates, and m6A RNA Methylation Regulators in Esophageal Squamous Cell Carcinoma

et al. 2021

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BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most common cancer types and represents a threat to global public health. N6-Methyladenosine (m6A) methylation plays a key role in the occurrence and development of many tumors, but there are still few studies investigating ESCC. This study attempts to construct a prognostic signature of ESCC based on m6A RNA methylation regulators and to explore the potential association of these regulators with the tumor immune microenvironment (TIME).MethodsThe transcriptome sequencing data and clinical information of 20 m6A RNA methylation regulators in 453 patients with ESCC (The Cancer Genome Atlas [TCGA] cohort, n = 95; Gene Expression Omnibus [GEO] cohort, n = 358) were obtained. The differing expression levels of m6A regulators between ESCC and normal tissue were evaluated. Based on the expression of these regulators, consensus clustering was performed to investigate different ESCC clusters. PD-L1 expression, immune score, immune cell infiltration and potential mechanisms among different clusters were examined. LASSO Cox regression analysis was utilized to obtain a prognostic signature based on m6A RNA methylation modulators. The relationship between the risk score based on the prognostic signature and the TIME of ESCC patients was studied in detail.ResultsSix m6A regulators (METTL3, WTAP, IGF2BP3, YTHDF1, HNRNPA2B1 and HNRNPC) were observed to be significantly highly expressed in ESCC tissues. Two molecular subtypes (clusters 1/2) were determined by consensus clustering of 20 m6A modulators. The expression level of PD-L1 in ESCC tissues increased significantly and was significantly negatively correlated with the expression levels of YTHDF2, METL14 and KIAA1429. The immune score, CD8 T cells, resting mast cells, and regulatory T cells (Tregs) in cluster 2 were significantly increased. Gene set enrichment analysis (GSEA) shows that this cluster involves multiple hallmark pathways. We constructed a five-gene prognostic signature based on m6A RNA methylation, and the risk score based on the prognostic signature was determined to be an independent prognostic indicator of ESCC. More importantly, the prognostic value of the prognostic signature was verified using another independent cohort. m6A regulators are related to TIME, and their copy-number alterations will dynamically affect the number of tumor-infiltrating immune cells.ConclusionOur study established a strong prognostic signature based on m6A RNA methylation regulators; this signature was able to accurately predict the prognosis of ESCC patients. The m6A methylation regulator may be a key mediator of PD-L1 expression and immune cell infiltration and may strongly affect the TIME of ESCC.

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“…Treatment with 10 μM melatonin maintained the stemness features of ESCs for more than 90 days (45 passages) via the marked suppression of global m 6 A modification and significant reduction in m 6 A “writer” METTL3 [ 1050 ]. Melatonin treatment decreased m 6 A mRNA methylation and altered the subcellular location of METTL3, preventing m 6 A-dependent mRNA decay to stabilize key pluripotency factors Nanog, Sox2, Klf4, and c-Myc [ 1050 ], known to be destabilized by m 6 A methylation [ 1051 ]. It has been proposed that melatonin could decrease METTL3, increasing ESC pluripotency via the MT1-JAK2/STAT3-Zfp217 signal axis.…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

“…Zinc finger protein 217 (ZFP217) has been reported to activate pluripotency genes and sequester METTL3 [ 1052 ]. Using doxycycline to induce an 85% knockdown of ZFP217 in ESCs treated with melatonin, or the depletion of melatonin receptor 1 (MT1), failed to produce similar effects of m 6 A modification compared to wild-type ESCs treated with melatonin [ 1050 ]. However, if knocking down ZFP217 (reduction in ATP by 25% in prostate cancer cells [ 1053 ]) and/or using doxycycline (~80% reduction in ATP in hypoxic stem-like prostate cancer cells [ 1054 ]) lowered ATP production in ESCs used in the experiment [ 1050 ], then it is possible that even in the presence of melatonin, the lack of ATP led to the failure of DDX3, an ATP-dependent helicase that regulates m 6 A mRNA methylation.…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

“…m 6 A mRNA methylation can be oxidatively reversed or “erased” by m 6 A demethylases such as FTO [ 976 , 1055 ] and ALKBH5 [ 973 , 1056 ]. Just as the suppression of METTL3 enhances ESC pluripotency [ 1050 ], the deficiency of “erasers” such as ALKBH5 is associated with testicular dysfunction, resulting in compromised spermatogenesis [ 1056 ]. In addition, the aberrant overexpression of ALKBH5 in AML enhances the self-renewal of leukemia stem/initiating cells, often resulting in poor prognosis in AML patients [ 1057 ].…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

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Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

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Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

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Melatonin restores the pluripotency of long‐term‐cultured embryonic stem cells through melatonin receptor‐dependent m6A RNA regulation

Cited by 30 publications

References 64 publications

Identification of an N6-methyladenosine-mediated positive feedback loop that promotes Epstein–Barr virus infection

Identification of an N6-methyladenosine-mediated positive feedback loop that promotes Epstein–Barr virus infection

Comprehensive Analysis of PD-L1 Expression, Immune Infiltrates, and m6A RNA Methylation Regulators in Esophageal Squamous Cell Carcinoma

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

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