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PCIF1 catalyzes m6Am mRNA methylation to regulate gene expression

ABSTRACT: PCIF1 catalyzes m6Am mRNA methylation to regulate gene expression

PROVIDER: PRJNA506407 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8234010.fastq.gz	Fastqsanger.gz
	SRR8234020.fastq.gz	Fastqsanger.gz
	SRR8234030.fastq.gz	Fastqsanger.gz
	SRR8234040.fastq.gz	Fastqsanger.gz
	SRR8234050.fastq.gz	Fastqsanger.gz

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Similar Datasets

PCIF1 Catalyzes m6Am mRNA Methylation to Regulate Gene Expression.

Project description:mRNA modifications play important roles in regulating gene expression. One of the most abundant mRNA modifications is N6,2-O-dimethyladenosine (m6Am). Here, we demonstrate that m6Am is an evolutionarily conserved mRNA modification mediated by the Phosphorylated CTD Interacting Factor 1 (PCIF1), which catalyzes m6A methylation on 2-O-methylated adenine located at the 5' ends of mRNAs. Furthermore, PCIF1 catalyzes only 5' m6Am methylation of capped mRNAs but not internal m6A methylation in vitro and in vivo. To study the biological role of m6Am, we developed a robust methodology (m6Am-Exo-Seq) to map its transcriptome-wide distribution, which revealed no global crosstalk between m6Am and m6A under assayed conditions, suggesting that m6Am is functionally distinct from m6A. Importantly, we find that m6Am does not alter mRNA transcription or stability but negatively impacts cap-dependent translation of methylated mRNAs. Together, we identify the only human mRNA m6Am methyltransferase and demonstrate a mechanism of gene expression regulation through PCIF1-mediated m6Am mRNA methylation.

| S-EPMC6688901 | biostudies-literature

Identification of the m6Am Methyltransferase PCIF1 Reveals the Location and Functions of m6Am in the Transcriptome

Project description:mRNAs are regulated by nucleotide modifications that influence their cellular fate. Two of the most abundant modified nucleotides are N6-methyladenosine (m6A), found within mRNAs, and N6,2′-O-dimethyladenosine (m6Am), which is found at the first transcribed nucleotide. Distinguishing these modifications in mapping studies has been difficult. Here, we identify and biochemically characterize PCIF1, the methyltransferase that generates m6Am. We find that PCIF1 binds and is dependent on the m7G cap. By depleting PCIF1, we generated transcriptome-wide maps that distinguish m6Am and m6A. We find that m6A and m6Am misannotations arise from mRNA isoforms with alternative transcription start sites (TSSs). These isoforms contain m6Am that maps to “internal” sites, increasing the likelihood of misannotation. We find that depleting PCIF1 does not substantially affect mRNA translation but is associated with reduced stability of a subset of m6Am-annotated mRNAs. The discovery of PCIF1 and our accurate mapping technique will facilitate future studies to characterize m6Am’s function.

2019-07-03 | GSE122948 | GEO

METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing

Project description:METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing

| PRJNA604769 | ENA

The mammalian cap-specific m6Am RNA methyltransferase PCIF1 regulates transcript levels in mouse tissues

Project description:The 5' end of eukaryotic mRNAs is protected by the m7G-cap structure. The transcription start site nucleotide is ribose methylated (Nm) in many eukaryotes, while an adenosine at this position is further methylated at the N6 position (m6A) by the mammalian Phosphorylated CTD-interacting Factor 1 (PCIF1) to generate m6Am. Here we show that while loss of cap-specific m6Am in mice does not affect viability or fertility, the Pcif1 mutants display reduced body-weight. Transcriptome analyses of mutant mouse tissues support a role for the cap-specific m6Am modification in stabilizing transcripts. In contrast, the Drosophila Pcif1 is catalytically-dead, but like its mammalian counterpart it retains the ability to associate with the Ser5-phosphorylated CTD of RNA pol II. Finally, we show that the Trypanosoma Pcif1 is an m6Am methylase that contributes to the N6,N6,2?-O-trimethyladenosine (m62Am) in the hypermethylated cap4 structure of Trypanosomatids. Thus, PCIF1 has evolved to function in catalytic and non-catalytic roles.

2020-08-28 | GSE151229 | GEO

METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing

Project description:N6-methylation of 2’-O-methyladenosine (Am) in RNA occurs in eukaryotic cells to generate N6,2’-O-dimethyladenosine (m6Am). Identification of the methyltransferase responsible for m6Am catalysis has accelerated studies on the function of m6Am in RNA processing. While m6Am is generally found in the first transcribed nucleotide of mRNAs, the modification is also found internally within U2 snRNA. However, the writer required for catalyzing internal m6Am formation had remained elusive. By sequencing transcriptome-wide RNA methylation at single-base-resolution, we identified human METTL4 as the writer that directly methylates Am at U2 snRNA position 30 into m6Am. We found that METTL4 localizes to the nucleus and its conserved methyltransferase catalytic site is required for U2 snRNA methylation. By sequencing human cells with overexpressed Mettl4, we determined METTL4’s in vivo target RNA motif specificity. In the absence of Mettl4 in human cells, U2 snRNA lacks m6Am thereby affecting a subset of splicing events that exhibit specific features such as overall 3’ splice-site weakness with certain motif positions more affected than others. This study establishes that METTL4 methylation of U2 snRNA regulates splicing of specific pre-mRNA transcripts.

2020-08-17 | GSE144745 | GEO

m6Am RNA methylation enzyme PCIF1 restricts HIV infection and is degraded by viral Vpr protein

Project description:To identify m6Am genes that are responsible for HIV inhibition, MeRIP-seq was performed in control and PCIF1 KO T cells infected with HIV.

2021-08-09 | GSE154035 | GEO

PCIF1 catalyzes m6Am mRNA methylation to regulate gene expression

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-06-01 | GSE122803 | GEO

HIV reprograms host m6Am RNA methylome by viral Vpr protein-mediated degradation of PCIF1

Project description:To identify m6Am genes that are responsible for HIV inhibition, m6Am-exo-seq was performed in control, PCIF1 KO T cells, and cells infected with HIV.

2021-08-09 | GSE171800 | GEO

METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing.

Project description:N 6-methylation of 2'-O-methyladenosine (Am) in RNA occurs in eukaryotic cells to generate N6,2'-O-dimethyladenosine (m6Am). Identification of the methyltransferase responsible for m6Am catalysis has accelerated studies on the function of m6Am in RNA processing. While m6Am is generally found in the first transcribed nucleotide of mRNAs, the modification is also found internally within U2 snRNA. However, the writer required for catalyzing internal m6Am formation had remained elusive. By sequencing transcriptome-wide RNA methylation at single-base-resolution, we identified human METTL4 as the writer that directly methylates Am at U2 snRNA position 30 into m6Am. We found that METTL4 localizes to the nucleus and its conserved methyltransferase catalytic site is required for U2 snRNA methylation. By sequencing human cells with overexpressed Mettl4, we determined METTL4's in vivo target RNA motif specificity. In the absence of Mettl4 in human cells, U2 snRNA lacks m6Am thereby affecting a subset of splicing events that exhibit specific features such as 3' splice-site weakness and an increase in exon inclusion. These findings suggest that METTL4 methylation of U2 snRNA regulates splicing of specific pre-mRNA transcripts.

| S-EPMC7498333 | biostudies-literature

The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to govern anti-tumor immunity

Project description:T cell-based cancer immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here, we report that PCIF1, an RNA N6, 2’-O-dimethyladenosine (m6Am) methyltransferase, negatively regulates CD8+ T cell anti-tumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) significantly reduces tumor growth in mice. Single-cell RNA sequencing reveals heightened tumor-infiltrating cytotoxic CD8+ T cells in Pcif1-deficient mice. Mechanistically, proteomic and m6Am-sequencing analyses pinpoint that Pcif1 KO elevates crucial m6Am-modified targets, specifically ferroptosis suppressor genes (Fth1, Slc3a2), and T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8+ T cell activation. Of note, Pcif1-deficient mice with tumors exhibit enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO CAR T cells demonstrate improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells exhibit enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8+ T cell activation and targeting PCIF1 as a promising strategy to boost anti-tumor immunity.

2024-11-14 | GSE254597 | GEO

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