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The yeast RNA methylation complex consists of conserved yet reconfigured components with m6A-dependent and independent roles

ABSTRACT: N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/drosophila/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis but was known to comprise three proteins, of which two were conserved in mammals. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian orthologs. Nonetheless, the yeast MTC is arranged differently from its mammalian counterpart. The yeast MTC features a mostly mutually stabilizing core comprising Ime4/Mum2/Vir1 and the mRNA binding component Kar4, and an auxiliary hub comprising Slz1/Dyn2. The MTC core subunits when in a complex have both m6A-dependent and m6A-independent functions in meiosis. Kar4 also has a mechanistically separate function from the MTC during mating. Our findings expand the relevance of yeast as a model for unravelling m6A-dependent and independent functions of MTCs.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE224637 | GEO | 2023/07/19

REPOSITORIES: GEO

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The yeast RNA methylation complex consists of conserved yet reconfigured components with m6A-dependent and independent roles [RNA-Seq]

Project description:N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/drosophila/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis but was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologs. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The MTC’s mRNA interacting core, comprising Ime4, Mum2, Vir1, and Kar4, is critical for the m6A-independent function in meiosis, while the MTC’s catalytic activity is enabled by Slz1 during meiosis. Kar4 also has a mechanistically separate function from the MTC during mating. Our findings demonstrate that the yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent and-independent functions, highlighting its complexity and paving the path to dissecting the multi-layered functions in mammals.

2023-06-15 | GSE224833 | GEO

The yeast RNA methylation complex consists of conserved yet reconfigured components with m6A-dependent and independent roles [m6A-Seq]

Project description:N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/insects/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis and was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologs. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The mRNA interacting module, comprising Ime4, Mum2, Vir1, and Kar4, exerts the MTC m6A-independent function, while Slz1 enables the MTC catalytic function in m6A deposition. Both functions are critical for meiotic progression. Kar4 also has a mechanistically separate role from the MTC during mating. The yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent and MTC-independent functions, highlighting their complexity and paving the path towards dissecting multi-layered MTC functions in mammals.

2023-06-15 | GSE224835 | GEO

The yeast RNA methylation complex consists of conserved yet reconfigured components with m6A-dependent and independent roles

Project description:This SuperSeries is composed of the SubSeries listed below. Abstract: N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/insects/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis and was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologs. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The mRNA interacting module, comprising Ime4, Mum2, Vir1, and Kar4, exerts the MTC m6A-independent function, while Slz1 enables the MTC catalytic function in m6A deposition. Both functions are critical for meiotic progression. Kar4 also has a mechanistically separate role from the MTC during mating. The yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent and MTC-independent functions, highlighting their complexity and paving the path towards dissecting multi-layered MTC functions in mammals.

2023-06-15 | GSE224836 | GEO

BRD4 ChIP-seq in JQ1 treatment and control in MDA-MB-231 cells.

Project description:Aberrant expression of m6A writer complex has been reported across human cancers, resulting in abnormal m6A epitranscriptome that drives tumorigenesis. But the regulatory mechanism remains unknown. Here, we identified an unappreciated interplay between the histone acetyl-lysine reader BRD4 and the m6A methyltransferase complex (MTC) across human cancers. BRD4 directly stimulates transcript expression of seven MTC subunits, allowing the maintenance of nuclear METTL3/METTL14 abundance and the formation of functional writer complex to catalyze m6A modification.

2023-12-31 | GSE219192 | GEO

Yeast meiotic proteome in wildtype versus kar4 mutant

Project description:The Kar4 protein has been identified as being a component of the yeast N6A mRNA methyltransferase, homologous to human METTL14. Mutations in KAR4 cause blocks in meiosis due to 1) reduced expression of Ime1p-induced transcripts, and 2) reduced levels of a subset of meiotic proteins, independent of their transcript levels. The reduced levels of the proteins are partially suppressed by increased levels of a translational regulator, Rim4. This proteomic study was aimed at identifying the spectrum of meiotic proteins affected by the absence of Kar4. The defect in Ime1p-depedent transcription was suppressed by over-expression of Ime1p. Proteins present in wildtype and kar4 deletion strains at two different times in meiosis were fractionated using reverse-phase chromatography and identified by MS/MS. Some 4068 proteins expressed during meiosis were identified. At 8 hours, 432 proteins were present at less than 50% the levels in kar4Δ/Δ compared to wild type. GO term analysis of the low proteins at 8 hours returned “meiotic cell cycle” as the sixth term with a P value of 7.74x10^-5. At 12 hours, 318 proteins were present at less than 50% the levels in kar4Δ/Δ relative to wild type. GO term analysis returned “meiotic cell cycle” as the second term with a P value less than 0.001. Proteins that were low at both 8 and 12 hours in kar4∆/∆ comprise proteins required for meiotic recombination and sporulation including Sps2p, Gas4p, Gmc2p, Mei5p, and Sae3p. Other meiotic proteins were expressed at or above wild type levels at 8 hours, but went down to lower than wild type levels at 12 hours, including Ecm11p, Hed1p, Spo11p, and Rec8p. In each case the levels of the proteins were reduced to much greater extents that can be explained by changes in transcript levels. Taken together these data suggest that Kar4 plays a role in the regulation of transcription and translation during yeast meiosis.

2023-08-22 | PXD043798 | Pride

LC-MS/MS analysis of co-immunoprecipitation products of METTL3

Project description:N6-methyladenosine (m6A) methylation of mRNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the mechanism of MTC assembly remains elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3), that is highly expressed in breast cancer. Furthermore, we find that both METTL3a and full-length METTL3 are required for MTC assembly, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is required for METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC assembly. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A methylation, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Consequently, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component for MTC assembly, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

2023-08-18 | PXD036899 | Pride

Magnetic-Targeted Doxorubicin in Treating Patients With Cancer Metastatic to the Liver

Project description:MTC-DOX is Doxorubicin or DOX, a chemotherapy drug, that is adsorbed, or made to "stick", to magnetic beads (MTCs). MTCs are tiny, microscopic particles of iron and carbon. When DOX is added to MTCs, DOX attaches to the carbon part of the MTCs. MTC-DOX is directed to and deposited in the area of a tumor, where it is thought that it then "leaks" through the blood vessel walls. Once in the surrounding tissues, it is thought that Doxorubicin becomes "free from" the magnetic beads and will then be able to act against the tumor cells. The iron component of the particle has magnetic properties, making it possible to direct MTC-DOX to specific tumor sites in the liver by placing a magnet on the body surface. It is hoped that MTC-DOX used with the magnet may target the chemotherapy drug directly to liver tumors and provide a treatment to patients with cancers that have spread to the liver.

| 2007949 | ecrin-mdr-crc

Integration of miRNA, mRNA and methylation profiling reveals genes aberrantly regulated associated to RETM918T mutation in Medullary Thyroid Carcinoma [methylation component]

Project description:Medullary thyroid carcinoma (MTC) accounts for 1-2% of thyroid malignancies. It is a disease of few genetic drivers, and the etiology specifically associated with each mutation remains unknown. Here, we investigated the role of aberrant DNA methylation in the MTC development. We performed genome-wide DNA methylation profiling assessing >27,000 CpGs in the largest MTC series reported to date, comprising 48 molecularly characterized tumors. We observed significant differences between the methylation patterns among the samples bearing the RETM918T, RETC634 mutation and “wild-type” (WT) tumors, but not those RAS-related. In detail, the RETM918T –related tumors had a larger number of hypomethylation events when compared to RETC634 – positive and WT ones. Moreover, through the integration of methylation with mRNA and miRNA expression data of the same tumors, we identified genes whose expression is negatively correlated with the methylation status of their promoters. For PLCB2, DKK4, MMP20 as well as miR-10a, -30a and -200c, the impact of promoter methylation levels on expression of these genes in MZ-CRC-1 and TT cell lines was assessed. Finally, the aberrant methylation validation of three of the genes in an independent set of 25 MTCs by bisulfite pyrosequencing suggests their role as MTC methylation markers.

2016-12-31 | GSE72729 | GEO

Integration of miRNA, mRNA and methylation profiling reveals genes aberrantly regulated associated to RETM918T mutation in Medullary Thyroid Carcinoma [miRNA component]

2016-12-31 | GSE72728 | GEO

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq

Project description:This SuperSeries is composed of the following subset Series: GSE36958: Gene expression profiles of WT and ime4-/- mutant yeast cells, under vegetative and meiosis-inducing conditions GSE37001: METTL3 KD in HepG2 cells GSE37002: m6A mapping in human RNA (with treatments) GSE37003: m6A mapping in human RNA (untreated) GSE37004: m6A mapping in mouse RNA (mouse liver and human brain) Refer to individual Series

2012-04-24 | E-GEOD-37005 | biostudies-arrayexpress

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