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N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms.

ABSTRACT: As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m⁶A) is involved in a wide range of physiological and pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, and YTHDF3, are a class of cytoplasmic m⁶A-binding proteins defined by the vertebrate YTH domain, and exert extensive functions in regulating RNA destiny. Distinct expression patterns of the YTHDF family in specific cell types or developmental stages result in prominent differences in multiple biological processes, such as embryonic development, stem cell fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, and tumorigenesis. The YTHDF family mediates tumor proliferation, metastasis, metabolism, drug resistance, and immunity, and possesses the potential of predictive and therapeutic biomarkers. Here, we mainly summary the structures, roles, and mechanisms of the YTHDF family in physiological and pathological processes, especially in multiple cancers, as well as their current limitations and future considerations. This will provide novel angles for deciphering m⁶A regulation in a biological system.

SUBMITTER: Chen L

PROVIDER: S-EPMC10043241 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms.

Chen Lin L Gao Yang Y Xu Simiao S Yuan Jinxiong J Wang Min M Li Tianyu T Gong Jun J

Frontiers in immunology 20230314

As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m<sup>6</sup>A) is involved in a wide range of physiological and pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, and YTHDF3, are a class of cytoplasmic m<sup>6</sup>A-binding proteins defined by the vertebrate YTH domain, and exert extensive functions in regulating RNA destiny. Distinct expression patterns of the YTHDF family in ...[more]

PMID: 36999016

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Project description:BackgroundA number of studies have demonstrated that N6-methyladenosine (m6A) plays a vital role in the pathological process of various tumours. Recently, it was found that m6A writers or erasers affect the tumourigenesis of melanoma. However, the relationship between m6A readers such as YTH domain family (YTHDF) proteins and melanoma was still elusive.MethodsRT-qPCR, Western blot and immunohistochemistry were conducted to measure the expression level of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) and lysyl oxidase-like 3 (LOXL3) in melanoma tissues and cells. The effects of YTHDF3 and LOXL3 on melanoma were verified in vitro and in vivo. Multi-omics analysis including RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses was performed to identify the target. The interaction between YTHDF3 and LOXL3 was verified by RT-PCR, Western blot, MeRIP-qPCR, RIP-qPCR and CRISPR-Cas13b-based epitranscriptome engineering.ResultsIn this study, we found that m6A reader YTHDF3 could affect the metastasis of melanoma both in vitro and in vivo. The downstream targets of YTHDF3, such as LOXL3, phosphodiesterase 3A (PDE3A) and chromodomain helicase DNA-binding protein 7 (CHD7) were identified by means of RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses. Besides, RT-qPCR, Western blot, RIP-qPCR and MeRIP-qPCR were performed for subsequent validation. Among various targets of YTHDF3, LOXL3 was found to be the optimal target of YTHDF3. With the application of CRISPR-Cas13b-based epitranscriptome engineering, we further confirmed that the transcript of LOXL3 was captured and regulated by YTHDF3 via m6A binding sites. YTHDF3 augmented the protein expression of LOXL3 without affecting its mRNA level via the enrichment of eukaryotic translation initiation factor 3 subunit A (eIF3A) on the transcript of LOXL3. LOXL3 downregulation inhibited the metastatic ability of melanoma cells, and overexpression of LOXL3 ameliorated the inhibition of melanoma metastasis caused by YTHDF3 downregulation.ConclusionsThe YTHDF3-LOXL3 axis could serve as a promising target to be interfered with to inhibit the metastasis of melanoma.

Project description:Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.

Dataset Information

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms.

Publications

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms.

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