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Homo sapiens

ABSTRACT: The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention

PROVIDER: PRJNA356403 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5080310_1.fastq.gz	Fastqsanger.gz
	SRR5080310_2.fastq.gz	Fastqsanger.gz
	SRR5080301_1.fastq.gz	Fastqsanger.gz
	SRR5080301_2.fastq.gz	Fastqsanger.gz
	SRR5080311_1.fastq.gz	Fastqsanger.gz

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The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention

Project description:Maintenance of the intracellular levels of the methyl donor S-adenosylmethionine (SAM) is essential for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of MAT2A, which encodes the only SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3´ UTR. Increasing METTL16 occupancy on the MAT2A 3´ UTR is sufficient to induce efficient splicing. We propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which in turn promotes MAT2A splicing. Interestingly, human and S. pombe METTL16 methylate the U6 spliceosomal snRNA at a sequence identical to hp1. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

2017-05-18 | GSE90914 | GEO

METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs

Project description:N6-methyladenosine (m6A) is a highly dynamic RNA modification that has recently emerged as a key regulator of gene expression. While many m6A modifications are installed by the METTL3-METTL14 complex, others appear to be introduced independently, implying that additional human m6A methyltransferases remain to be identified. Using crosslinking and analysis of cDNA (CRAC), we reveal that the putative human m6A “writer” protein METTL16 binds to the U6 snRNA and other ncRNAs as well as numerous lncRNAs and pre-mRNAs. We demonstrate that METTL16 is responsible for N6-methylation of A43 of the U6 snRNA and identify the early U6 biogenesis factors La, LARP7 and the methylphosphate capping enzyme MEPCE as METTL16-interaction partners. Interestingly, A43 lies within an essential ACAGAGA box of U6 that base pairs with 5’ splice sites of pre-mRNAs during splicing, suggesting that METTL16-mediated modification of this site plays an important role in splicing regulation. The identification of METTL16 as an active m6A methyltransferase in human cells expands our understanding of the mechanisms by which the m6A landscape is installed on cellular RNAs.

2017-10-19 | GSE103948 | GEO

Methylation of structured RNA by the m6A writer METTL16 is essential for mouse embryonic development

Project description:Internal modification of RNAs with N6-methyladenosine (m6A) is a highly conserved and widely used means of gene expression control. METTL16 is an m6A writer but how it recognizes its RNA targets and its physiological roles remain unknown. Here we describe the crystal structure of human METTL16 to reveal a classical methyltransferase domain but with an extra N-terminal module that is essential for catalysis. Together, they form a deep-cut groove lined by highly conserved positively charged residues that are essential for RNA binding and methylation activity. When given a random pool of RNAs, METTL16 selects structured RNAs for m6A methylation. We demonstrate that mouse Mettl16 is essential for early embryonic development, and acts via regulation of the SAM synthetase Mat2a mRNA. Our results highlight the pivotal role of an m6A RNA methyltransferase in facilitating early developmental decisions via regulation of SAM availability.

2018-09-12 | GSE116329 | GEO

RNA Methyltransferase METTL16’s Protein Domains Have Differential Functional Effects on Cell Processes

Project description:METTL16, a human m6A RNA methyltransferase, contains multiple RNA binding domains and is known to modify U6 and MAT2A RNAs. Usingmutagensis, we generated HEK293 cell lines stabling expressing nutated or WT forms of METTL16 to dtermine the imapct these mutations have on cell processes after removal of endogenous METTL16. We performed bottom-up, untargeted data dependent proteomics analysison all five cell lines to determine the global changes in peptide/protein abdundances; we identified 200-300 statistically significant altered proteinscompared to the wild-type exogenous METTL16 clone.

2023-10-24 | PXD042242 | Pride

RNA m6A methylation of 3ʹ splice site prevents binding of U2AF35 to inhibit splicing

Project description:OThe N6-methyladenosine (m6A) RNA modification is widely used to alter the fate of mRNAs. Here we demonstrate that the C. elegans writer METT-10 (orthologue of mouse METTL16) deposits an m6A mark on the 3′ splice site (AG) of the SAM synthetase pre-mRNA which inhibits its proper splicing and protein production. The mechanism is triggered by a rich diet, and acts as an m6A-mediated switch to stop SAM production and regulate its homeostasis. Although the mammalian SAM synthetase pre-mRNA is not regulated via this mechanism, we show that splicing inhibition by 3′ splice site m6A is conserved in mammals. The modification functions by physically preventing the essential splicing factor U2AF35 from recognizing the 3′ splice site. We propose that use of splice site m6A is an ancient mechanism for splicing regulation.

2021-04-29 | GSE146873 | GEO

The role and mechanism of METTL16 in Alzheimer's disease

Project description:Mettl16 regulates SAM homeostasis by mediating m6A modification of MAT2A mRNA and participates in the pathogenesis of Alzheimer's disease.

2022-03-03 | PXD032022 |

CRISPR screen identifies NUDT21 as a regulator of intron detention of the SAM synthetase MAT2A RNA

Project description:The only S-adenosymethionine (SAM) synthetase expressed in most human cells, MAT2A, is regulated by intron detention. Using a GFP fusion reporter, we conducted a CRISPR screen to identify regulators of this alternative splicing event. The screen identified METTL16, a known regulator of this process, and NUDT21. NUDT21 encodes the CFIm25 protein a member of the CFIm complex involved in alternative polyadenylation. Validation and follow-up studies support the idea that CFIm25 and the larger CFIm complex plays an unanticipated role in splicing of the MAT2A detained intron.

2021-05-04 | GSE172217 | GEO

Identifying interaction proteins of METTL16 using co immunoprecipitation and mass spectroscopy

Project description:METTL16 has recently been identified as an RNA methyltransferase that installs m6A marks on a few transcripts. But its function in cytosol remains unclear. Puromycin-labelling and renilla luciferase assay revealed that METTL16 can promote translation efficiency in an m6A-independent manner. To explore the mechanism, we performed co-immunoprecipitation using METTL16 antibody and mass spectroscopy to identify its interaction proteins. Moreover, we find that METTL16 is essential for tumorigenesis of non-small cell lung cancer.

2024-08-03 | PXD032068 | Pride

RNA-seq in wild-type, METTL16-knockout, and METTL16 rescue NOMO-1 cells

Project description:METTL16 belongs to methyltransferase like (METTL) family and could install m6A marks on its substrates. Here, we uncover a tumor-promoting role of METTL16 in AML and LSC self-renewal. To explore the mechanism underlying the oncogenic function of METTL16 in AML, we performed m6A-seq and RNA-seq. Via integrated analysis of m6A-seq data and RNA-seq data, we identified two bona fide targets of METTL16, BCAT1 and BCAT2. METTL16 functions as an m6A methyltransferase to regulate expression of BCAT1 and BCAT2, which contribute to reprogramming BCAA metabolism.

2023-01-12 | GSE190044 | GEO