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The 18S rRNA m6A 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 (m6A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. The m6A mark also resides in the decoding center of 18S ribosomal RNA (rRNA), however, the biological function of m6A 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, m6A deposited by METTL5 regulates 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 m6A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m6A.

SUBMITTER: Ms. Ming Xing

PROVIDER: S-SCDT-EMBOR-2019-49863V1 | biostudies-other |

REPOSITORIES: biostudies-other

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The 18S rRNA m6A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation

Project description:Input mRNAs and ribosome protected fragments (RPFs) from wildtype and Mettl5 knockout (KO) mESC cells were analyzed by TruSeq Ribo Profile (Illumina) library preparation and high throughput sequencing

2020-08-03 | GSE138341 | GEO

The 18S rRNA m<sup>6</sup> A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation.

Project description: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.

| S-EPMC7534618 | biostudies-literature

The 18S rRNA m6A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation

Project description:The 18S rRNA m6A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation

| PRJNA575537 | ENA

The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112.

Project description:N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m6A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here, we identify METTL5 as the enzyme responsible for 18S rRNA m6A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5-TRMT112, supporting that its RNA-binding mode differs distinctly from that of other m6A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5-TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.

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18S rRNA methyltransferase EMG1 non-enzymatically influence m6A in mRNA

Project description:Defects in ribosome biogenesis can trigger a battery of cellular events to alter gene expression and cell growth. 18S rRNA methyltransferase EMG1 is an important assembly factor in ribosome biogenesis. Here, we report that downregulation of EMG1 non-enzymatically leads to decreased N6-methyladensine (m6A) levels in polyadenylated RNA. We revealed the identities of the messenger RNAs with decreased m6A intensities upon EMG1 deficiency using m6A-IP-seq. This group of mRNAs significantly overlap with the CLIP targets of IGF2BP3, which is an m6A reader protein stabilizing m6A-containing transcripts. Furthermore, both RNA-seq and qRT-PCR results suggest that the expression level of this group of mRNAs significantly decreased upon EMG1 deficiency, possibly through the regulation of IGF2BP3. Gene ontology analysis suggests that this group of mRNAs function in a list of cell signaling pathways important for cell growth. These findings collectively suggest that decreased ribosome assembly may influence gene expression via decreasing m6A levels in mRNAs.

2023-12-15 | GSE190945 | GEO

The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112

Project description:N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m6A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here we identify METTL5 as the enzyme responsible for 18S rRNA m6A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5-TRMT112, supporting that its RNA binding mode differs distinctly from that of other m6A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5-TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.

2019-07-15 | GSE128699 | GEO

METTL5, an 18S rRNA-specific m6A methyltransferase, regulates the Integrated Stress Response [eCLIP]

Project description:RNA N6-methyladenosine (m6A) modification is present in different RNA molecules, including protein-coding mRNAs and non-coding RNAs such as ribosomal RNAs (rRNAs).Here, we report that mammalian METTL5, a member of a highly conserved methyltransferase family, specifically methylates adenosine 1832 (A1832) in the 18S rRNA in vivo and in vitro.

2020-09-17 | GSE138123 | GEO

METTL5, an 18S rRNA-specific m6A methyltransferase, modulates expression of stress response genes

Project description:Input mRNAs and ribosome protected fragments (RPFs) from wildtype and Mettl5 knockout (KO) B16 cells were analyzed by TruSeq Ribo Profile (Illumina) library preparation and high throughput sequencing

2020-04-28 | GSE138110 | GEO

Rapamycin efficiently promotes cardiac differentiation of mouse embryonic stem cells.

Project description:To investigate the effects of rapamycin on cardiac differentiation, murine embryonic stem cells (ESCs) were induced into cardiomyocytes by 10-4 M ascorbic acid (AA), 20 nM rapamycin alone or 0.01% solvent DMSO. We found that rapamycin alone was insufficient to initiate cardiomyogenesis. Then, the ESCs were treated with AA and rapamycin (20 nM) or AA and DMSO (0.01%) as a control. Compared with control, mouse ESCs (mESCs) treated with rapamycin (20 nM) and AA yielded a significantly higher percentage of cardiomyocytes, as confirmed by the percentage of beating embryonic bodies (EBs), the immunofluorescence and FACS analysis. Rapamycin significantly increased the expression of a panel of cardiac markers including Gata4, ?-Mhc, ?-Mhc, and Tnnt2. Additionally, rapamycin enhanced the expression of mesodermal and cardiac transcription factors such as Mesp1, Brachyury T, Eomes, Isl1, Gata4, Nkx2.5, Tbx5, and Mef2c. Mechanistic studies showed that rapamycin inhibits Wnt/?-catenin and Notch signaling but promotes the expression of fibroblast growth factor (Fgf8), Fgf10, and Nodal at early stage, and bone morphogenetic protein 2 (Bmp 2) at later stages. Sequential treatment of rapamycin showed that rapamycin promotes cardiac differentiation at the early and later stages. Interestingly, another mammalian target of rapamycin (mTOR) inhibitor Ku0063794 (1 µM) had similar effects on cardiomyogenesis. In conclusion, our results highlight a practical approach to generate cardiomyocytes from mESCs by rapamycin.

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Superhero Rictor promotes cellular differentiation of mouse embryonic stem cells.

Project description:Embryonic stem cells (ESCs) hold great promise for regenerative medicine. To harness the full therapeutic potential of ESCs, better understanding of the molecular mechanisms underlying the maintenance and differentiation of ESCs is required. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that integrates growth factor receptor signaling with cellular growth and proliferation. Dysregulation of mTOR signaling has been linked to various human diseases including cancer and metabolic syndromes. However, little is known regarding the function of mTOR signaling in the regulation of ES cell differentiation. Here we report that Rictor, a key component of mTORC2, functions as a novel ES cell differentiation promoting factor. Mechanistically, Rictor is able to interact with Prkch and facilitate Prkch phosphorylation at Ser-642. Upon phosphorylation, Prkch promotes Klf4 phosphorylation and inhibits Klf4-dependent E-cadherin expression, thereafter leading to the ES cell differentiation. These findings reveal a novel Rictor-Prkch-Klf4 pathway that plays an important role in the regulation of ES cell differentiation.

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