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Rbfox2-dependent alternative splicing of Numb regulates Notch signaling during muscle stem cell activation

ABSTRACT: Satellite cells (SCs), or muscle stem cells, are the resident somatic stem cells responsible for skeletal muscle regeneration. Most SCs remain quiescent in resting adult muscles but can activate rapidly upon receiving a stimulus. While Rbfox2 has been reported to play an essential role in regulating myoblast differentiation, its role in the activation process of SCs remains elusive. To investigate the role of Rbfox2 during satellite cell activation, we freshly isolated satellite cells from Rbfox2 conditional knockout mice and performed RNA-seq to profile the transcriptome changes upon Rbfox2 knockout.

ORGANISM(S): Mus musculus

PROVIDER: GSE263621 | GEO | 2025/12/30

REPOSITORIES: GEO

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Rbfox2-dependent alternative splicing of Numb regulates Notch signaling during muscle stem cell activation II

Project description:Satellite cells (SCs), or muscle stem cells, are the resident somatic stem cells responsible for skeletal muscle regeneration. Most SCs remain quiescent in resting adult muscles but can activate rapidly upon receiving a stimulus. While alternative splicing has been reported to play important role in stem cells , its role in the activation process of SCs remains elusive. We identified Numb as one of the genes that display rapid splicing change during SC activation. To investigate the role of Numb splicing during satellite cell activation, we use morpholino to inhibit the inculstion of Numb exon 6 on early activated SCs and performed RNA-seq to profile the transcriptome changes upon Numb splicing change.

2025-12-30 | GSE290586 | GEO

Three-dimensional tissue-engineered human skeletal muscle model of satellite cell quiescence

Project description:In vivo, satellite cells (SCs) are essential for skeletal muscle repair. However, in vitro investigation of SC function is challenged by isolation-induced SC activation, loss of the native quiescent state, and differentiation to myoblasts. This study applies tissue-engineered human skeletal muscle to track myoblast deactivation to 3D-SCs, which bear a quiescent phenotype, as well as examine melittin-induced injury response.

2021-11-11 | GSE188215 | GEO

Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis

Project description:Purpose: The goals of this study are to compare transcriptomes using RNA-seq of mouse myoblasts (C2C12 cell line) in undifferentiated and differentiated states and with siRNA-mediated knock down of the RNA binding proteins, Rbfox1 (only expressed in differentiated state) and Rbfox2 (expressed in both undifferentiated and differentiated states). Methods: Differentiated and undifferentiated C2C12 cultures treated with Rbfox1 (differentiated only) or Rbfox2 siRNAs or a mock siRNA transfection were used for RNA-Seq analysis using Illumina HiSeq2000. 101x2 paired-end RNA-seq reads were first uniquely aligned to the mouse genome (mm9) using TopHat 1.4.1. RSEM was used to count the number of reads mapped to genes using UCSC database, followed by edgeR to call differentially expressed genes with false discovery rate less than 0.01. Cufflinks was used to reconstruct isoforms and analyze alternative splicing and percent spliced in (PSI) was calculated. PSI values were validated by RT-PCR. Results: 58-88% of the RNA-seq reads from technical and biological replicates mapped uniquely to the mouse genome. Analysis of gene expression and alternative splicing changes are published in Singh et al. Molecular Cell (2014). Conclusions: Our study has identified gene expression and alternative splicing transitions that occur during myoblast differentiation, demonstrate that 30% of the splicing transitions are regulated by Rbfox2, demonstrated that Rbfox2 is required for a late step of myoblast differentiation and identified two Rbfox2-regulated splicing transitions that are required for differentiation. Undifferentiated and differentiated C2C12 cultures with Rbfox2 depletion or Rbfox1 depletion (differentiated only) in at least duplicate samples analyzed by deep sequencing on Illumina HiSeq2000.

2014-07-15 | E-GEOD-58928 | biostudies-arrayexpress

Lockd promotes myoblast proliferation and skeletal muscle regeneration through binding with DHX36 to facilitate unwinding of 5’UTR rG4 and translation of Anp32e mRNA

Project description:Adult muscle stem cells, also known as satellite cells (SCs) play pivotal roles in injury induced muscle regeneration and our knowledge of long non-coding RNA (lncRNA) functions in SCs remains limited. Here we identify a lncRNA, Lockd which is induced in activated SCs upon acute muscle injury. We demonstrate that Lockd promotes SC proliferation; deletion of Lockd leads to cell cycle arrest at G1/S phase. Consistently, in vivo repression of Lockd in mouse muscles hinders muscle regeneration process. Mechanistically, we uncover that Lockd lncRNA molecule directly interacts with an RNA helicase DHX36; structural probing further shows that the 5’end of the Lockd possesses the strongest binding activity with DHX36 protein. Furthermore, we demonstrate that Lockd stabilizes the interaction between DHX36 and EIF3B proteins; and synergistically this complex unwinds the RNA G-quadruplex (rG4) structure formed at the 5’UTR of Anp32e mRNA and promotes the translation of ANP32E protein which is required for myoblast cell proliferation. Altogether, our findings thus identify a regulatory circuitry consisting of Lockd/DHX36/Anp32e that functions to promote myoblast proliferation, thus enabling the acute injury induced muscle regeneration to progress.

2022-05-24 | PXD033658 |

Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control (RNA-Seq)

Project description:Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease. We then performed gene expression profiling analysis using data obtained from RNA-seq of primary myoblast from total muscle of WT and eIF5A KO mice.

2024-10-08 | GSE221641 | GEO

Rbfox2 controls autoregulation in RNA binding protein networks

Project description:We generated a global analysis of Rbfox2 splicing regulation combined with a highly specific, single nucleotide-resolution Rbfox2 RNA binding map. We found that Rbfox2 regulates the splicing and expression of many previously unknown targets, and particularly a number of RNA binding proteins (RBPs), by modulating alternative splicing coupled-NMD. Based on our observations of RBP-Rbfox2 co-regulation with a polarity predicted by Rbfox2 binding, we propose a model whereby Rbfox2 tunes autoregulatory splicing events to control RBP expression levels and in turn alter their respective splicing networks. iCLIP for epitope-tagged Rbfox2 and control untagged Rbfox2; RNAseq of control and Rbfox2 knockdown in mouse embryonic stem cells

2014-03-17 | E-GEOD-54794 | biostudies-arrayexpress

Long noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly

Project description:Long non-coding RNAs (lncRNAs) are family of gene regulators but the functional study of lncRNAs in skeletal muscle satellite cells (SCs) remains at the infancy stage. Here we identify SAM (Sugt1 associated muscle) lncRNA (also known as Snhg15, (small nucleolar RNA host gene 15) that is enriched in the proliferating myoblast cells and down-regulated as the cells progressed to differentiation. Gain- or loss- of function of SAM in muscle SCs alters myogenic proliferation and differentiation. Global deletion of SAM based on the KO-first strategy has no overt effect on mice but impairs adult muscle regeneration following acute damage; the loss also exacerbates the chronic injury induced dystrophic phenotype in the mdx mouse model. Consistently, inducible deletion of SAM in adult SCs leads to deficiency in acute injury-induced muscle regeneration. Further examination of SCs revealed that SAM loss results in cell autonomous defect in proliferative expansion of myoblasts. Mechanistically, we find SAM interacts and stabilizes Sugt1 (suppressor of G2 allele of SKP1) protein, a co-chaperon protein key to kinetochore assembly during cell division. Loss of SAM or Sugt1 both cause disruptive kinetochore assembly and microtubule attachment in mitotic cells due to mis-localization of key components Dsn1 and Hec1 proteins. Altogether, our findings identify SAM as a regulator of SC proliferation through facilitating Sugt1 mediated kinetochore assembly during cell division.

2020-05-18 | PXD018147 | Pride

Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis

2014-07-15 | GSE58928 | GEO

Overexpression of the non-muscle RBFOX2 isoform triggers cardiac conduction defects in myotonic dystrophy

Project description:Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG trinucleotide repeat expansion in the 3′ untranslated region of DMPK gene. Heart dysfunctions occur in nearly 80% of DM1 patients and are the second leading cause of disease-related deaths, yet, the underlying mechanisms remain unclear. Herein, we report that upregulation of a non-muscle splice isoform of RNA binding protein RBFOX2 in DM1 heart tissue—due to altered splicing factor and microRNA activities—induces the characteristic cardiac conduction defects detected in DM1 individuals. Mice engineered to express the non-muscle RBFOX2 isoform in heart via tetracycline- inducible transgenesis, or CRISPR/Cas9 targeted genome editing, reproduced DM1- related cardiac-conduction delay and spontaneous episodes of arrhythmia. Furthermore, by integrating RNA binding with cardiac transcriptome datasets of DM1 patients, and mice expressing the non-muscle RBFOX2 isoform, we identified a core network of RBFOX2-driven splicing defects in sodium, potassium, and calcium channels that can alter their rate of ion diffusion and electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX2 isoform in DM1 cardiac pathogenesis.

2020-03-10 | GSE126771 | GEO

RNAseq of livers from WT mice or livers with Rbfox2 knockout fed CD

Project description:Rbfox2 is required for maintaining hepatic metabolic homeostasis, here we carry out RNAseq to of WT and aged matched littermate Rbfox2 knockout mice under high fructose in order to determine changes in alternative splicing and mRNA expression caused by knockout of this splicing factor in this metabolic environment.

2022-09-26 | GSE151748 | GEO

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