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METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [Ribo-seq]

ABSTRACT: METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [Ribo-seq]

PROVIDER: PRJNA927820 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23229746_1.fastq.gz	Fastqsanger.gz
	SRR23229746_2.fastq.gz	Fastqsanger.gz
	SRR23229747_1.fastq.gz	Fastqsanger.gz
	SRR23229747_2.fastq.gz	Fastqsanger.gz
	SRR23229748.fastq.gz	Fastqsanger.gz

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Similar Datasets

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [Ribo-seq]

Project description:RNA splicing dysregulation is a hallmark of cancers, promoting the onset and progression of disease. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ~20% of patients. However, the underlying mechanism for splicing defects in spliceosome unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover proteins involved in RNA splicing are post-transcriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing (factors) complexes is an independent risk factor and associated with poor prognosis in CLL. Moreover, increased splicing factor expression is highly correlated with METTL3, an RNA methyltransferase that modifies N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo, and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification mediated ribosome recycling and decoding process. Our results uncover a novel regulatory axis of METTL3 for splicing dysregulation in CLL and highlight m6A modification as a major contributor to spliceosome mutation-independent splicing defects that lead to CLL progression.

2023-03-03 | GSE223730 | GEO

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [MeRIP-seq]

2023-03-03 | GSE223729 | GEO

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [RNA-seq]

2023-03-03 | GSE223728 | GEO

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression

Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression

| PRJNA927575 | ENA

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [MeRIP-seq]

Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [MeRIP-seq]

| PRJNA927821 | ENA

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [RNA-seq]

Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [RNA-seq]

| PRJNA927494 | ENA

METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL.

Project description:RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.SignificanceMETTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171.

| S-EPMC10150290 | biostudies-literature

RNA-seq and Ribo-seq analysis of the effects of METTL3/14 depletion on gene expression during the interferon response in Huh7 cells

Project description:The RNA modification N6-methyladenosine (m6A) regulates gene expression through various transcript-specific effects. The overall goal of these experiments was to determine the effects of the m6A methyltransferase complex proteins METTL3 and METTL14 on the expression of interferon stimulated genes. First, we depleted METTL3 and METTL14 in Huh7 cells using siRNAs and treated with Mock or IFN-β to analyze the regulatory effects of METTL3/14 on interferon-stimulated genes' transcript abundance. We then used Ribo-seq following METTL3/14 siRNA depletion and IFN treatment to quantify its effect on the translation of ISGs and other genes. Overall, we found that METTL3/14 exerts transcript-specific regulatory effects on a subset of interferon-stimulated genes. Overall, METTL3/14 appeared to enhance the translation of a subset of interferon-stimulated genes. We characterized the molecular effects of METTL3/14 and m6A on certain ISGs and determined that m6A augments the antiviral effects of the interferon response.

2021-02-19 | GSE155447 | GEO

METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression

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

2023-03-03 | GSE223731 | GEO

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

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