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Mettl16 promotes hematopoietic stem and progenitor cell expansion in embryonic hematopoiesis [RNA-seq]

ABSTRACT: The RNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of vertebrate embryogenesis and malignancies. However, its functions and underlying molecular mechanisms in the expansion of hematopoietic stem and progenitor cells (HSPCs) during early embryonic development remain elusive. Here we show that Mettl16, an RNA methyltransferase identified recently, is specifically required for HSPC expansion during zebrafish early embryonic development in an m6A-dependent manner. In mettl16 deficient embryos, HSPCs exhibit defective proliferation capacity due to G0/G1 arrest. Mechanistically, HSPC proliferation is blocked by impaired methyltransferase function of Mettl16 in vivo. We identify cell cycle gene mybl2b as a novel direct m6A target of Mettl16, and Mettl16 deficiency destabilizes mybl2b mRNA, which is mediated by m6A reader Igf2bp1. Moreover, we revealed that the METTL16-m6A-MYBL2-IGF2BP1 signaling axis in G1/S progression is conserved in humans. Collectively, our findings demonstrate the critical function of m6A modification deposited by Mettl16 in HSPC expansion during early embryonic development.

ORGANISM(S): Danio rerio

PROVIDER: GSE225089 | GEO | 2024/03/04

REPOSITORIES: GEO

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Mettl16 promotes hematopoietic stem and progenitor cell expansion in embryonic hematopoiesis [m6A-Seq]

Project description:The RNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of vertebrate embryogenesis and malignancies. However, its functions and underlying molecular mechanisms in the expansion of hematopoietic stem and progenitor cells (HSPCs) during early embryonic development remain elusive. Here we show that Mettl16, an RNA methyltransferase identified recently, is specifically required for HSPC expansion during zebrafish early embryonic development in an m6A-dependent manner. In mettl16 deficient embryos, HSPCs exhibit defective proliferation capacity due to G0/G1 arrest. Mechanistically, HSPC proliferation is blocked by impaired methyltransferase function of Mettl16 in vivo. We identify cell cycle gene mybl2b as a novel direct m6A target of Mettl16, and Mettl16 deficiency destabilizes mybl2b mRNA, which is mediated by m6A reader Igf2bp1. Moreover, we revealed that the METTL16-m6A-MYBL2-IGF2BP1 signaling axis in G1/S progression is conserved in humans. Collectively, our findings demonstrate the critical function of m6A modification deposited by Mettl16 in HSPC expansion during early embryonic development.

2024-03-04 | GSE225136 | 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

Next Generation Sequencing (m6A-seq) Reveals RNA m6A Methylation Patterns During the floral transition of Arobidopsis

Project description:In this study, we identified METTL16 as an mRNA m6A methyltransferase that plays a vital role in the floral transition in Arabidopsis. Transcriptome-wide analysis of RNA methylome in the mettl16 mutant revealed that m6A modification enriched near the stop codon and within the 3ʹ untranslated region. Deficiency of METTL16 leads to decreases in m6A levels of approximately 471 transcripts, indicating that it is responsible for the methylation of a small group of mRNAs. The mettl16 mutant displayed an early flowering phenotype, and the level of FLOWERING LOCUS C (FLC) was markedly decreased in the mutant. Importantly, METTL16-mediated m6A methylation affects the splicing of FLC, thereby influencing its transcript level to regulate floral transition. Our study identified METTL16 as a novel m6A methyltransferase and suggests a close molecular link between METTL16-mediated m6A methylation and FLC splicing in flowering time control.

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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.

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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

Determine the methyltransferase activities of METTL16 via MeRIP-seq (m6A-seq)

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Identification of osteolineage cell-derived extracellular vesicle cargo implicated in hematopoietic support

Project description:Osteolineage cell-derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non-stimulatory osteolineage EVs by next-generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV-derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood-derived CD34+ HSPCs with stimulatory EVs altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study gives novel insights into the complex biological role of EVs in osteolineage cell-HSPC crosstalk and promotes the utility of EVs and their cargo as therapeutic agents in regenerative medicine.

2020-02-28 | PXD017172 | Pride

Determine METTL16-mediated spatiotemoral installation of m6A via MeRIP-seq (m6A-seq) with nascent RNA and nuclear poly(A) RNA

Project description:METTL16 belong to methyltransferase like (METTL) family and possesses the ability to deposit N6-methyladenosine (m6A) in mRNA. We have conducted m6A-seq with poly(A) RNAs isolated from the whole HEK293T cells upon METTL16 knockdown to identify the transcripts with hypo m6A peaks after METTL16 knockdown, and also conducted RIP-seq with HEK293T cells to determine the METTL16-bound transcripts. However, we found that the transcripts with hypo m6A peaks upon METTL16 knockdown only account for a small proportion of METTL16-bound transcripts. We suppose one of the possibility reasons might be due to spatiotemporal installation of m6A. To support our hypothesis, we performed additional m6A seq with nascent RNA and nuclear poly(A) RNA isolated from HEK293T cells with METTL16 knockdown.

2021-10-28 | GSE156795 | 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.

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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

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