Abstract
Within the glioblastoma cellular niche, glioma stem cells (GSCs) can give rise to differentiated glioma cells (DGCs) and, when necessary, DGCs can reciprocally give rise to GSCs to maintain the cellular equilibrium necessary for optimal tumor growth. Here, using ribosome profiling, transcriptome and m6A RNA sequencing, we show that GSCs from patients with different subtypes of glioblastoma share a set of transcripts, which exhibit a pattern of m6A loss and increased protein translation during differentiation. The target sequences of a group of miRNAs overlap the canonical RRACH m6A motifs of these transcripts, many of which confer a survival advantage in glioblastoma. Ectopic expression of the RRACH-binding miR-145 induces loss of m6A, formation of FTO/AGO1/ILF3/miR-145 complexes on a clinically relevant tumor suppressor gene (CLIP3) and significant increase in its nascent translation. Inhibition of miR-145 maintains RRACH m6A levels of CLIP3 and inhibits its nascent translation. This study highlights a critical role of miRNAs in assembling complexes for m6A demethylation and induction of protein translation during GSC state transition.
Highlights
N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNA and depends on methyltransferases for reversible m6A post-transcriptional installment within the consensus sequence of G(m6A)C (70%) or A(m6A)C (30%)[1,2]
Cellular plasticity and epigenetic adaptation of human glioblastoma stem cells to the tumor microenvironment is a hallmark of this devastating disease
We discover the relationship between miRNAs and the RNA methylation machinery in human glioblastoma and show how miRNA-induced loss of m6A results in increase in protein translation of clinically important transcripts during glioblastoma stem cell differentiation
Summary
N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNA and depends on methyltransferases for reversible m6A post-transcriptional installment within the consensus sequence of G(m6A)C (70%) or A(m6A)C (30%)[1,2]. Recent seminal findings show that m6A placement on a given transcript significantly contributes to its fate, marking it for degradation or stabilization and impacting translation outcome[5] Such discoveries have led to increased interest in m6A regulation as it relates to various disease processes. We integrate RNAseq, meRIP-seq and ribo-seq in stem and differentiated cells from three different patient derived samples representing defined GBM subtypes (mesenchymal, proneural and classical). Using these integrated data, we perform an unsupervised comparative analysis between stem and differentiated cell states in order to uncover how m6A changes relate to translation during the process of cellular differentiation
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