Intron retention decreases METTL3 expression by inhibiting mRNA export to the cytoplasm
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Methyltransferase-like 3 (METTL3), a key component of the m6Amethyltransferase complex, regulates the splicing, nuclear transport,stability, and translation of its target genes. However, themechanism underlying the regulation of METTL3 expressionby alternative splicing (AS) remains unknown. We analyzedthe expression pattern of METTL3 after AS in human tissues andconfirmed the expression of an isoform retaining introns 8 and9 (METTL3-IR). We confirmed the different intracellular localizationsof METTL3-IR and METTL3 proteins using immunofluorescencemicroscopy. Furthermore, the endogenous expressionof METTL3-IR at the protein level was different from that at themRNA level. We found that 3’-UTR generation by intron retention(IR) inhibited the export of METTL3-IR mRNA to thecytoplasm, which in turn suppressed protein expression. Tothe best of our knowledge, this is the first study to confirm theregulation of METTL3 gene expression by AS, providing evidencethat the suppression of METTL3 protein expression byIR is an integral part of the mechanism by which 3’-UTR generationregulates protein expression via inhibition of RNA exportto the cytoplasm.
Abstract
Methyltransferase-like 3 (METTL3), a key component of the m6Amethyltransferase complex, regulates the splicing, nuclear transport,stability, and translation of its target genes. However, themechanism underlying the regulation of METTL3 expressionby alternative splicing (AS) remains unknown. We analyzedthe expression pattern of METTL3 after AS in human tissues andconfirmed the expression of an isoform retaining introns 8 and9 (METTL3-IR). We confirmed the different intracellular localizationsof METTL3-IR and METTL3 proteins using immunofluorescencemicroscopy. Furthermore, the endogenous expressionof METTL3-IR at the protein level was different from that at themRNA level. We found that 3’-UTR generation by intron retention(IR) inhibited the export of METTL3-IR mRNA to thecytoplasm, which in turn suppressed protein expression. Tothe best of our knowledge, this is the first study to confirm theregulation of METTL3 gene expression by AS, providing evidencethat the suppression of METTL3 protein expression byIR is an integral part of the mechanism by which 3’-UTR generationregulates protein expression via inhibition of RNA exportto the cytoplasm.
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