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The 18S rRNA m⁶ A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation.

ABSTRACT: RNA modifications represent a novel layer of regulation of gene expression. Functional experiments revealed that N⁶ -methyladenosine (m⁶ A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. m⁶ A mark also resides in the decoding center of 18S ribosomal RNA (rRNA); however, the biological function of m⁶ A on 18S rRNA is still poorly understood. Here, we report that methyltransferase-like 5 (METTL5) methylates 18S rRNA both in vivo and in vitro, which is consistent with previous reports. Deletion of Mettl5 causes a dramatic differentiation defect in mouse embryonic stem cells (mESCs). Mechanistically, the m⁶ A deposited by METTL5 is involved in regulating the efficient translation of F-box and WD repeat domain-containing 7 (FBXW7), a key regulator of cell differentiation. Deficiency of METTL5 reduces FBXW7 levels and leads to the accumulation of its substrate c-MYC, thereby delaying the onset of mESC differentiation. Our study uncovers an important role of METTL5-mediated 18S m⁶ A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m⁶ A.

SUBMITTER: Xing M

PROVIDER: S-EPMC7534618 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRibosomal RNA N6-methyltransferase METTL5 was reported to catalyze m6A in 18S rRNA. We aimed to investigate the expression and prognostic features of METTL5 in gastric cancer (GC).MethodsIn this study, 168 GC patients and their corresponding adjacent tissues were collected. Immunohistochemical staining was used to detect the expression of METTL5 protein. Univariate and multivariate Cox analysis were used to dertermine the prognostic role of METTL5 protein in GC, and a nomogram was constructed to evaluate GC patients' prognosis based on METTL5 expression. Data from TCGA and GEO database were also used to validate the prognostic value of METTL5 in GC patients on mRNA level. We further performed GSEA enrichment analysis to explore the possible function and related pathways related to METTL5.ResultsMETTL5 protein in gastric cancer tissues (GCTs) was significantly decreased compared with adjacent normal tissues (ANTs) and adjacent intestinal metaplasia tissues (AIMTs) (P < 0.001, respectively). Meanwhile, METTL5 expression was negatively correlated with clinicopathologic stage. According to multivariate Cox proportional hazards model analysis, METTL5 protein expression was a good independent predictor of GC prognosis (p < 0.05). Patients with high METTL5 expression had better prognosis. The nomogram constructed based on METTL5 expression could predict the prognosis of GC patients well. GSEA analysis showed that genes of METTL5 low expression group were enriched in some oncogenic signaling pathways such as ERBB, MAPK, JAK-STAT, Wnt, and mTOR, as well as some immune pathways, including Fc-gamma R mediated phagocytosis, Fc-epsilon Ri, chemokine, T cell receptor and B cell receptor signaling pathway. While the high expression group of METTL5 was mainly related to oxidative phosphorylation, nucleotide excision repair and mismatch repair.ConclusionsMETTL5 protein was decreased in GCTs compared with AIMTs and ANTs, and it may be a potential prognostic biomarker in GC.

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The 18S rRNA m⁶ A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation.

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The 18S rRNA m6 A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation.

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OmicsDI is part of the ELIXIR infrastructure

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The 18S rRNA m⁶ A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation.