Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

Lou, Chih Hong; Shao, Ada; Shum, Eleen Y.; Espinoza, Josh L.; Huang, Lulu; Karam, Rachid; Wilkinson, Miles

doi:10.1016/j.celrep.2014.01.028

Cited by 140 publications

(187 citation statements)

References 48 publications

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“…In addition, evidence suggests that NMD participates in regulation of normal gene expression by targeting a subset of normally processed mRNAs (Mendell et al 2004;Wittmann et al 2006;Viegas et al 2007;Huang et al 2011;Yepiskoposyan et al 2011;Tani et al 2012;Hurt et al 2013). Consistent with this, NMD contributes to important biological processes such as neuronal differentiation, myogenesis, T lymphocyte maturation, and inhibition of viral replication (Weischenfeldt et al 2008;Gong et al 2009;Bruno et al 2011;Frischmeyer-Guerrerio et al 2011;Balistreri et al 2014;Lou et al 2014).…”

Section: Introductionmentioning

confidence: 71%

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

Toma

Rebbapragada

Durand

et al. 2015

RNA

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The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3 ′ UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3 ′ UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3 ′ UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3 ′ UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMDinhibiting cis elements in the first 200 nt. A smaller subset of long 3 ′ UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3 ′ UTRs.

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Section: Introductionmentioning

confidence: 71%

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

Toma

Rebbapragada

Durand

et al. 2015

RNA

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“…4). Perhaps NMD activity was compromised during stem cell differentiation (36). Instead, RBM4 could induce the expression of the exon 9-skipping PTB isoform without affecting overall PTB protein expression in MSCs.…”

Section: Discussionmentioning

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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“…However, NMD also targets a significant fraction of apparently normal and physiologically functional wild-type mRNAs (Schweingruber et al 2013), indicating that it also serves as a fundamental posttranscriptional regulatory mechanism for eukaryotic gene expression. Consistent with these important roles, NMD function is linked to diverse cellular processes, including cell growth and proliferation (Weischenfeldt et al 2008;Avery et al 2011;Lou et al 2014), development and differentiation (Medghalchi et al 2001;Metzstein and Krasnow 2006;Gong et al 2009;Wittkopp et al 2009), innate immunity (Gloggnitzer et al 2014), antiviral or stress responses (Sakaki et al 2012;Balistreri et al 2014), and neuronal activity or behavior (Giorgi et al 2007;Colak et al 2013).…”

Section: Introductionmentioning

confidence: 99%

High-resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection

Çelik

Baker

et al. 2017

RNA

100

140

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Nonsense-mediated mRNA decay (NMD) plays an important role in eukaryotic gene expression, yet the scope and the defining features of NMD-targeted transcripts remain elusive. To address these issues, we reevaluated the genome-wide expression of annotated transcripts in yeast cells harboring deletions of the UPF1, UPF2, or UPF3 genes. Our new RNA-seq analyses confirm previous results of microarray studies, but also uncover hundreds of new NMD-regulated transcripts that had escaped previous detection, including many intron-containing pre-mRNAs and several noncoding RNAs. The vast majority of NMD-regulated transcripts are normal-looking protein-coding mRNAs. Our bioinformatics analyses reveal that this set of NMD-regulated transcripts generally have lower translational efficiency and higher ratios of out-of-frame translation. NMD-regulated transcripts also have lower average codon optimality scores and higher transition probability to nonoptimal codons. Collectively, our results generate a comprehensive catalog of yeast NMD substrates and yield new insights into the mechanisms by which these transcripts are targeted by NMD.

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Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

Cited by 140 publications

References 48 publications

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

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

High-resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection

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