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

Su, Chunping; Hung, Kuan-Yang; Hung, Shih‐Chieh; Tarn, Woan‐Yuh

doi:10.1128/mcb.00466-16

Cited by 40 publications

(39 citation statements)

References 38 publications

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“…To explain why hyperactive Nrf2 selectively up-regulated Pkm2 expression, we examined the expression of hnRNPA1, hnRNPA2, RBM4, and PTB, which were known to regulate alternative splicing of the Pkm gene (35,36). As expected, the Keap1 Ϫ/Ϫ esophagus expressed higher levels of hnRNPA1, hnRNPA2, and PTB and a lower level of RBM4 than WT esophagus ( Fig.…”

Section: Hyperactive Nrf2 In the Esophagusmentioning

confidence: 66%

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Xiong

Huang

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan WangMutations in the genes encoding nuclear factor (erythroidderived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2 ؊/؊ , Keap1 ؊/؊ , K5Cre;Pkm2 fl/fl ;Keap1 ؊/؊ , and WT) and analyzed for metabolomic profiles, Nrf2 ChIP-seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro. In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2 high ESCC in humans.Esophageal cancer affects 16,940 adults in the United States, and the 5-year survival rate is 18% (1). There are mainly two histological types of esophageal cancer, squamous cell carcinoma (ESCC) 4 and adenocarcinoma, each having a distinct etiology. Low income, moderate/heavy alcohol intake, tobacco use, and infrequent consumption of raw fruits and vegetables account for almost all cases of ESCC (2). With the recent technological advances in NextGen sequencing, human ESCC samples from North and South America, China, Japan, Vietnam, and Malawi have been sequenced. Among many gene mutations, nuclear factor (erythroid-derived 2)-like 2 (NRF2 or NFE2L2) mutations are commonly seen with a frequency over 5%, even up to ϳ20% in certain reports. Mutations in other genes of the NRF2 signaling pathway, Kelch-like ECH associated protein 1 (KEAP1) and cullin 3 (CUL3), are relatively less common. NRF2 mutations are mostly located in the DLG and ETGE motifs (KEAP1-binding domain) and the DNA-binding domain, whereas KEAP1 mutations tend to be scattered across the whole gene. NRF2 mutations and KEAP1 mutations tend to be mutually exclusive (3,4).As a major cellular defense mechanism, the NRF2 signaling pathway is known to regulate expression of enzymes involved in detoxification and ant...

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Section: Hyperactive Nrf2 In the Esophagusmentioning

confidence: 66%

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Xiong

Huang

et al. 2019

Journal of Biological Chemistry

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“…RBM4 antagonizes PTBP1 function in regulating alternative splicing of Dab1. RBM4 regulates mRNA splicing essentially through binding to CU-rich motifs (8,9,10,11). The above data (Fig.…”

Section: Rbm4 Deficiency Impairs Dab1 Isoform Expression In the Develmentioning

confidence: 66%

“…The protein RNA-binding motif 4 (RBM4) is a splicing regulator with binding preference for CU-rich sequences (8,9,10,11). RBM4 regulates alternative splicing programs that impact differentiation of various cell types (8,9,12).…”

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confidence: 99%

“…We previously reported that RBM4 modulates alternative splicing of the Notch signaling inhibitor Numb and that RBM4-induced Numb isoforms potentiate the expression of the proneurogenesis gene Mash1 and hence promotes differentiation of mouse neuronal progenitor cells (15). In addition, RBM4 modulates the splice isoform switch of pyruvate kinase M (PKM) and thereby elevates mitochondrial oxidative phosphorylation and facilitates neuronal differentiation of mesenchymal stem cells (10). Mammalian genomes have two adjacent copies of Rbm4 (Rbm4a and Rbm4b) (8).…”

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confidence: 99%

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RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development

Dhananjaya

Hung

Tarn

2018

Molecular and Cellular Biology

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The RNA-binding motif 4 (RBM4) protein participates in cell differentiation via its role in regulating the expression of tissue-specific or developmentally regulated mRNA splice isoforms. RBM4 is expressed in embryonic brain during development; it is initially enriched in the ventricular zone/subventricular zone and subsequently distributed throughout the cerebral cortex. knockout brain exhibited delayed migration of late-born neurons. Using electroporation, we confirmed that knockdown of RBM4 impaired cortical neuronal migration. RNA immunoprecipitation with high-throughput sequencing identified (), which encodes a critical reelin signaling adaptor, as a potential target of RBM4. knockout embryonic brain showed altered isoform ratios. Overexpression of RBM4 promoted the inclusion of exons 7 and 8 (7/8), whereas its antagonist polypyrimidine tract-binding protein 1 (PTBP1) acted in an opposite manner. RBM4 directly counteracted the effect of PTBP1 on exon 7/8 selection. Finally, we showed that the full-length Dab1, but not exon 7/8-truncated Dab1, rescued neuronal migration defects in RBM4-depleted neurons, indicating that RBM4 plays a role in neuronal migration via modulating the expression of Dab1 splice isoforms. Our findings imply that RBM4 is necessary during brain development and that its deficiency may lead to developmental brain abnormality.

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“…In addition to evolutionary conservation, ubiquitous expression, and above mentioned apparent auto-regulation, RBM4's functional importance is further highlighted by the fact that gnomAD v.2.1 (51) -the largest collection of human genome sequences to date containing data from over 141,000 subjects -does not currently contain a single case of homozygous loss of function of RBM4. RBM4 is commonly described as a splicing factor and a tumor suppressor, yet, there are only a few anecdotal examples of RBM4-mediated, consequential alternative splicing (52)(53)(54)(55), and conflicting reports on its association with cancer outcomes (56,57).…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

Foroushani

Chim

Wong

et al. 2020

Preprint

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The human genome encodes for over 1,500 RNA-binding proteins (RBPs), which coordinate regulatory events on RNA transcripts (Gerstberger et al., 2014). Most studies of RBPs concentrate on their action on mRNAs that encode protein, which constitute a minority of the transcriptome. A widely neglected subset of our transcriptome derives from integrated retroviral elements termed endogenous retroviruses (ERVs) that comprise ~8% of the human genome. Some ERVs have been shown to be transcribed under physiological and pathological conditions suggesting that sophisticated regulatory mechanisms to coordinate and prevent their ectopic expression exist. However, it is unknown whether RBPs and ERV transcripts directly interact to provide a post-transcriptional layer of regulation. Here, we implemented a computational pipeline to determine the correlation of expression between individual RBPs and ERVs from single-cell or bulk RNA sequencing data. One of our top candidates for an RBP negatively regulating ERV expression was RNA-Binding Motif Protein 4 (RBM4). We used PAR-CLIP to demonstrate that RBM4 indeed bound ERV transcripts at CGG consensus elements. Loss of RBM4 resulted in elevated transcript level of bound ERVs of the HERV-K and -H families, as well as increased expression of HERV-K envelope protein. We pinpointed RBM4 regulation of HERV-K to a CGG-containing element that is conserved in the long terminal repeats (LTRs) of HERV-K-10 and -K-11, and validated the functionality of this site using reporter assays. In summary, we identified RBPs as potential regulators of ERV function and demonstrate a new role for RBM4 in controlling ERV expression.Significance StatementThe expression of endogenous retroviruses (ERVs) appears to have broad impact on human biology. Nevertheless, only a handful of transcriptional regulators of ERV expression are known and to our knowledge no RNA-binding proteins (RBPs) were yet implicated in positive or negative post-transcriptional regulation of ERVs. We implemented a computational pipeline that allowed us to identify RBPs that modulate ERV expression levels. Experimental validation of one of the prime candidates we identified, RBM4, showed that it indeed bound RNAs made from ERVs and negatively regulated the levels of those RNAs. We hereby identify a new layer of ERV regulation by RBPs.

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

Cited by 40 publications

References 38 publications

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

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