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

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

PROVIDER: PRJNA927494 | ENA |

REPOSITORIES: ENA

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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.

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

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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

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

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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]

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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.

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

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

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Mettl3-dependent m6A modification in postnatal liver

Project description:Liver-specific deficiency of Mettl3 causes liver injury. By performing RNA sequencing (RNA-seq) analysis on the Mettl3-deficient versus control livers, we identified the potential target genes that were closely associated with the liver phenotype in liver-specific Mettl3 knockout mice. RNA-seq analysis revealed extensive metabolic reprogramming in Mettl3-deficient livers. These results demonstrated that Mettl3 coordinates metabolic homeostasis and functional maturation during postnatal liver development.

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