The Splicing Factor RBM4 Controls Apoptosis, Proliferation, and Migration to Suppress Tumor Progression

Wang, Yang; Chen, Dan; Qian, Haili; Tsai, Yi-Hsuan; Shao, Shujuan; Liu, Quentin; Domínguez, Daniel; Wang, Zefeng

doi:10.1016/j.ccr.2014.07.010

Cited by 170 publications

(197 citation statements)

References 49 publications

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“…S4). Moreover, using publicly available CLIP and RNA-seq data for RBM4 (Uniacke et al 2012;Wang et al 2014), we find no evidence for significant binding or regulation of hnRNP L-enhanced exons by this protein. Therefore, while we cannot fully rule out the possibility that hnRNP L enhances exon inclusion through regulation of a secondary splicing factor, we find no evidence to support this model.…”

Section: Hnrnp L Uses Distinct Modes Of Enhancement and Repression Ofmentioning

confidence: 99%

Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons

Cole

Tapescu

Allon

et al. 2015

RNA

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HnRNP L is a ubiquitous splicing-regulatory protein that is critical for the development and function of mammalian T cells. Previous work has identified a few targets of hnRNP L-dependent alternative splicing in T cells and has described transcriptome-wide association of hnRNP L with RNA. However, a comprehensive analysis of the impact of hnRNP L on mRNA expression remains lacking. Here we use next-generation sequencing to identify transcriptome changes upon depletion of hnRNP L in a model T-cell line. We demonstrate that hnRNP L primarily regulates cassette-type alternative splicing, with minimal impact of hnRNP L depletion on transcript abundance, intron retention, or other modes of alternative splicing. Strikingly, we find that binding of hnRNP L within or flanking an exon largely correlates with exon repression by hnRNP L. In contrast, exons that are enhanced by hnRNP L generally lack proximal hnRNP L binding. Notably, these hnRNP L-enhanced exons share sequence and context features that correlate with poor nucleosome positioning, suggesting that hnRNP may enhance inclusion of a subset of exons via a cotranscriptional or epigenetic mechanism. Our data demonstrate that hnRNP L controls inclusion of a broad spectrum of alternative cassette exons in T cells and suggest both direct RNA regulation as well as indirect mechanisms sensitive to the epigenetic landscape.

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Section: Hnrnp L Uses Distinct Modes Of Enhancement and Repression Ofmentioning

confidence: 99%

Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons

Cole

Tapescu

Allon

et al. 2015

RNA

View full text Add to dashboard Cite

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“…4B). Both RBM4 and DAZAP1 were found to recognize ESS1 but had opposite activities in controlling exon inclusion in canonical splicing (Choudhury et al 2014;Wang et al 2014b). Consistently they showed opposite effects on the backsplicing of circRNA from ESS1-containing exon, although they also affected backsplicing of other minigenes in a sequence independent fashion (Fig.…”

Section: Backsplicing Of Circrna Is Regulated By Splicing Factorsmentioning

confidence: 99%

Efficient backsplicing produces translatable circular mRNAs

Wang

2014

RNA

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While the human transcriptome contains a large number of circular RNAs (circRNAs), the functions of most circRNAs remain unclear. Sequence annotation suggests that most circRNAs are generated from splicing in reversed orders across exons. However, the mechanisms of this backsplicing are largely unknown. Here we constructed a single exon minigene containing split GFP, and found that the pre-mRNA indeed produces circRNA through efficient backsplicing in human and Drosophila cells. The backsplicing is enhanced by complementary introns that form double-stranded RNA structure to bring splice sites in proximity, but such structure is not required. Moreover, backsplicing is regulated by general splicing factors and cis-elements, but with regulatory rules distinct from canonical splicing. The resulting circRNA can be translated to generate functional proteins. Unlike linear mRNA, poly-adenosine or poly-thymidine in 3 ′ UTR can inhibit circular mRNA translation. This study revealed that backsplicing can occur efficiently in diverse eukaryotes to generate circular mRNAs.

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“…T he splicing regulator RBM4 modulates alternative splicing of a number of transcripts involved in cell differentiation and tumorigenesis (1,2). Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3)(4)(5).…”

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confidence: 99%

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

Hung

et al. 2017

Molecular and Cellular Biology

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RBM4 promotes differentiation of neuronal progenitor cells and neurite outgrowth of cultured neurons via its role in splicing regulation. In this study, we further explored the role of RBM4 in neuronal differentiation. During neuronal differentiation, energy production shifts from glycolysis to oxidative phosphorylation. We found that the splice isoform change of the metabolic enzyme pyruvate kinase M (PKM) from PKM2 to PKM1 occurs during brain development and is impaired in RBM4-deficient brains. The PKM isoform change could be recapitulated in human mesenchymal stem cells (MSCs) during neuronal induction. Using a PKM minigene, we demonstrated that RBM4 plays a direct role in regulating alternative splicing of PKM. Moreover, RBM4 antagonized the function of the splicing factor PTB and induced the expression of a PTB isoform with attenuated splicing activity in MSCs. Overexpression of RBM4 or PKM1 induced the expression of neuronal genes, increased the mitochondrial respiration capacity in MSCs, and, accordingly, promoted neuronal differentiation. Finally, we demonstrated that RBM4 is induced and is involved in the PKM splicing switch and neuronal gene expression during hypoxiainduced neuronal differentiation. Hence, RBM4 plays an important role in the PKM isoform switch and the change in mitochondrial energy production during neuronal differentiation.KEYWORDS alternative splicing, hypoxia, mesenchymal stem cells, neuronal differentiation, pyruvate kinase M T he splicing regulator RBM4 modulates alternative splicing of a number of transcripts involved in cell differentiation and tumorigenesis (1, 2). Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3-5). We recently reported that RBM4 is also involved in neuronal differentiation of mouse embryonal carcinoma P19 cells and neural progenitor-derived cells (1). RBM4 promotes the expression of Numb splice isoforms that function during neuronal differentiation as well as neurite outgrowth. Mesenchymal stem cells (MSCs) are adult bone marrow stromal cells that can differentiate into a variety of cell types, including neurons, and have potential in regenerative therapy for neurological diseases (6). In this study, we assessed whether RBM4 can also modulate neuronal differentiation of MSCs and explored the underlying mechanism.Cellular energy metabolism undergoes a dynamic change during development. In principle, anabolic glycolysis dominates in embryonic stem cells and permits rapid cell proliferation similar to that in cancer cells (7,8). Most adult stem cells exhibit low glycolysis activity in a quiescent state and undertake active glycolysis while proliferat-

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The Splicing Factor RBM4 Controls Apoptosis, Proliferation, and Migration to Suppress Tumor Progression

Cited by 170 publications

References 49 publications

Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons

Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons

Efficient backsplicing produces translatable circular mRNAs

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

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