The crosstalk between m<sup>6</sup>A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling

Zhao, Yuechao; Chen, Yunhao; Jin, Mei Ling; Wang, Jin

doi:10.7150/thno.54967

Cited by 72 publications

(55 citation statements)

References 177 publications

(157 reference statements)

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“…In addition to mRNA, m 6 A and its regulators has also been found to affect the biological activity of other ncRNAs (55). METTL3-mediated m 6 A methylation on primary microRNA (pri-miRNA) are proved to promote the microRNA (miRNA) maturation in various pathophysiological processes (35,56,57).…”

Section: Regulatory Function Of M 6 Amentioning

confidence: 99%

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

Quan

Othmane

et al. 2021

Front. Immunol.

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N6-methylation of adenosine (m6A), a post-transcriptional regulatory mechanism, is the most abundant nucleotide modification in almost all types of RNAs. The biological function of m6A in regulating the expression of oncogenes or tumor suppressor genes has been widely investigated in various cancers. However, recent studies have addressed a new role of m6A modification in the anti-tumor immune response. By modulating the fate of targeted RNA, m6A affects tumor-associated immune cell activation and infiltration in the tumor microenvironment (TME). In addition, m6A-targeting is found to affect the efficacy of classical immunotherapy, which makes m6A a potential target for immunotherapy. Although m6A modification together with its regulators may play the exact opposite role in different tumor types, targeting m6A regulators has been shown to have wide implications in several cancers. In this review, we discussed the link between m6A modification and tumor with an emphasis on the importance of m6A in anti-tumor immune response and immunotherapy.

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Section: Regulatory Function Of M 6 Amentioning

confidence: 99%

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

Quan

Othmane

et al. 2021

Front. Immunol.

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“…m 6 A is a widely present methylation modi cation in mRNA, which is dynamic and reversible, involving in m 6 A methyltransferase, demethylase and recognition protein [19]. m 6 A participates in the regulation of mRNA nuclear export, splicing, stability, translation and degradation [20]. YTHDF1, belongs to YT521-B homology (YTH) domain family, is reported as a mRNA or translation regulator, some targets such as Myc [21], HINT2 [22], EIF3C [23]and TRAF6 [24].…”

Section: Discussionmentioning

confidence: 99%

HLA Complex P5 Upregulation Is Correlated With Poor Prognosis and Tumor Progression in Esophageal Squamous Cell Carcinoma

Wang

Shi

et al. 2021

Preprint

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Background: Esophageal squamous cell carcinoma (ESCC) is a deadly malignant tumor that threatens human health, especially in China. Long non-coding RNA (lncRNA) is widely expressed in eukaryotes and is closely associated with human disease progression. However, its role in ESCC remains incompletely understood. Here, we tested the role of HLA complex P5 (HCP5) in ESCC.Methods: Three GEO databases containing lncRNA expression data of ESCC and normal tissues were used to analyze the differentially expressed lncRNAs. The location of HCP5 was tested by qRT-PCR and FISH assays. The functional assay was detected by CCK-8, colony formation and Transwell assays. The HCP5/YTHDF1/HK2 axis was determined by RIP and RNA pull-down assays.Results: HCP5 was significantly overexpressed in ESCC tissues, which was further verified in our collected ESCC samples. The functional study suggested that HCP5 knockdown inhibited ESCC cell proliferation and invasion. Regarding the mechanism, HCP5 was able to directly interact with YTHDF1, a N6-methyladenosine (m6A) reader, enhancing the binding of YTHDF1 to m6A-modified HK2 mRNA, leading to increased HK2 stability, thereby promoting the Warburg effect (aerobic glycolysis) of ESCC cells. The nude mice model showed that knockdown of HCP5 in vivo remarkably reduced tumor size. Clinically, high HCP5 was positively correlated with larger tumor volume, higher TNM stage and lymph node metastasis. Moreover, ESCC patients with high HCP5 exerted shorter survival time than patients with low HCP5. Conclusion: These findings uncover the importance of HCP5 in human ESCC progression, the turbulence of HCP5/YTHDF1/HK2 axis may be responsible for ESCC carcinogenicity.

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“…In other words, epigenetic changes are those that tinker with gene activation but not the genetic code. Epigenetic mechanisms of gene regulation comprise DNA methylation, covalent posttranslational changes in histones, noncoding and messenger RNAs, and RNA modification [25,26]. Together, these definitions widen the possibility to describe and address acquired epigenetic changes as they occur along with development and aging.…”

Section: Chromatin Accessibility Gene Regulation and The Definition Of Epigeneticsmentioning

confidence: 99%

Epigenetics and Noncoding RNA – Principles and Clinical Impact

et al. 2021

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Genetics studies the inheritance of genetic information encoded by the base pair sequence and its variants. Sequence variants can have severe consequences as seen in genetically inherited diseases (e. g. osteogenesis Imperfecta, hypophosphatasia). On the other hand, epigenetics deals with inherited and dynamically reversible modifications of chromatin without changing the base pair sequence, resulting in a change in phenotype without a change in genotype. These modifications primarily exert their effects by influencing gene expression. Initially, the definition of epigenetics exclusively comprised inherited changes that persist across several generations without changes in the DNA sequence. This definition has been extended to include also dynamic and partially reversible changes that occur more short-term. These gene modulatory effects introduce new levels of complexity and are crucial determinants of cell fate and organismal development. With its length of approximately two meters, human DNA has to be compacted to fit into the nuclei and fulfill its functions. DNA is wrapped around histone octamers into so-called nucleosomes. DNA, histones, and other DNA-associated proteins together form what is called chromatin. DNA packaging is achieved by variable degrees of chromatin condensation depending on cell type and context. Epigenetic transcriptional regulation modifies the affinity and accessibility of cis-regulatory elements (CREs) for transcription factors and the basic transcriptional machinery and governs interaction between CREs. CREs include promoters, enhancers, silencers, and insulators and are potent modulators of gene expression impacting core cell biological processes such as proliferation and differentiation. Chromatin looping and remodeling by differential covalent modifications of DNA (e. g., methylation or hydroxylation) and histone tails (e. g., acetylation or methylation) elicit fundamental changes in CRE accessibility, thus impacting gene expression. Chromatin looping depends on a specialized machinery including cohesins. Chromatin modifications are mediated by specific enzymes like DNA methylases (DNMTs), histone-modifying enzymes, like histone methyl- and acetyltransferases (KMTs, HATs/KATs), and histone demethylases and deacetylases (KDMs, HDACs). It becomes increasingly evident that epigenetic (dys)regulation plays a decisive role in physiology and pathophysiology, impacting many age-related diseases like cancer and degenerative pathologies (e. g., osteoporosis, Alzheimer’s, or Parkinson’s) in a significant fashion. Recently, small-molecule inhibitors of chromatin-modifying enzymes (e. g., vorinostat) have been identified and successfully introduced in therapy. Significant progress in high-throughput sequencing technologies and big data analysis has broadened our understanding of noncoding (nc) RNAs and DNA sequence regions in (post-)transcriptional regulation and disease development. Among ncRNAs that play vital roles in gene expression are micro- (miRs) and long noncoding RNAs (lncRNAs; e. g., XIST or HOTAIR). By interacting with the coding genome, these RNAs modulate important genetic programs. Interfering RNAs can, for example, enhance the post-transcriptional degradation of transcripts, altering their translation, or assist in the recruitment of chromatin-modifying enzymes to regulate transcription. They can also be packaged into extracellular vesicles as cargo and thus deliver critical information to the microenvironment or even systemically to distant tissues. Therefore, ncRNAs represent a novel playground for therapeutical investigations and supplement epigenetic mechanisms of gene regulation while being subject to epigenetic regulation themselves. Last but not least, dysregulated ncRNAs can also propagate disease. Until recently, the detection of epigenetic phenomena necessitated invasive diagnostic interventions. However, with the arrival of so-called “liquid biopsies” an analysis of circulating cell-free DNA fragments (cfDNA) and RNAs as well as vesicle-packed RNAs through minimal invasively drawn blood samples can be obtained. Such “fragmentomics” and RNAomics approaches on peripheral blood will ultimately serve as diagnostic tools for personalized clinical interventions.

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The crosstalk between m⁶A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling

Cited by 72 publications

References 177 publications

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

HLA Complex P5 Upregulation Is Correlated With Poor Prognosis and Tumor Progression in Esophageal Squamous Cell Carcinoma

Epigenetics and Noncoding RNA – Principles and Clinical Impact

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The crosstalk between m6A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling

Cited by 72 publications

References 177 publications

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

HLA Complex P5 Upregulation Is Correlated With Poor Prognosis and Tumor Progression in Esophageal Squamous Cell Carcinoma

Epigenetics and Noncoding RNA – Principles and Clinical Impact

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The crosstalk between m⁶A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling