0.0 et al. 2023 (PRJNA927820)

General Details

Title METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [Ribo-seq]
Organism
Number of Samples 2
Release Date 2023/01/25 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP419131
ENA SRP419131
GEO GSE223730
BioProject PRJNA927820

Publication

Title
Authors Wu Y, Jin M, Fernandez M, Hart KL, Liao A, Ge X, Fernandes SM, McDonald T, Chen Z, Röth D, Ghoda LY, Marcucci G, Kalkum M, Pillai RK, Danilov AV, Li JJ, Chen J, Brown JR, Rosen ST, Siddiqi T, Wang L
Journal Blood cancer discovery
Publication Date 2023 May 1
Abstract 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. METTL3 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. ©2023 American Association for Cancer Research.
PMC PMC10150290
PMID 37067905
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR23229749 PRJNA927820 Homo sapiens HG3NA_chronic lymphocytic leukemia cell line Ribo-Seq 0.0
SRR23229748 PRJNA927820 Homo sapiens HG3NA_chronic lymphocytic leukemia cell line Ribo-Seq 0.0
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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