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FUS-mediated inhibition of myogenesis by suppressing TNNT1 production [RIP-seq]

ABSTRACT: Myogenesis is a highly orchestrated process whereby muscle precursor cells, myoblasts, develop into muscle fibers to form skeletal muscle during embryogenesis and regenerate adult muscle. Here, we studied the RNA-binding protein FUS (fused in sarcoma), which has been implicated in muscular and neuromuscular pathologies but is poorly characterized in myogenesis. Given that FUS levels declined in human and mouse models of skeletal myogenesis, and that silencing FUS enhanced myogenesis, we hypothesized that FUS might be a repressor of myogenic differentiation. Interestingly, overexpression of FUS delayed myogenesis, accompanied by slower production of muscle differentiation markers. To identify the mechanisms through which FUS inhibits myogenesis, we uncovered RNA targets of FUS by ribonucleoprotein immunoprecipitation (RIP) followed by RNA-sequencing (RNA-seq) analysis. Stringent selection of the bound transcripts uncovered Tnnt1 mRNA, encoding troponin T (TNNT1), as a major effector of FUS influence on myogenesis. We found that in myoblasts, FUS sequestered Tnnt1 mRNA in the nucleus, preventing TNNT1 expression; however, reduction of FUS during myogenesis or by silencing FUS released Tnnt1 mRNA for export to the cytoplasm, where it accumulated and was translated into TNNT1, promoting myogenesis. We propose that FUS inhibits myogenesis by suppressing TNNT1 expression through a mechanism of nuclear mRNA retention.

ORGANISM(S): Mus musculus

PROVIDER: GSE267277 | GEO | 2024/09/13

REPOSITORIES: GEO

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FUS-mediated inhibition of myogenesis by suppressing TNNT1 production [RNA-seq]

Project description:Myogenesis is a highly orchestrated process whereby muscle precursor cells, myoblasts, develop into muscle fibers to form skeletal muscle during embryogenesis and regenerate adult muscle. Here, we studied the RNA-binding protein FUS (fused in sarcoma), which has been implicated in muscular and neuromuscular pathologies but is poorly characterized in myogenesis. Given that FUS levels declined in human and mouse models of skeletal myogenesis, and that silencing FUS enhanced myogenesis, we hypothesized that FUS might be a repressor of myogenic differentiation. Interestingly, overexpression of FUS delayed myogenesis, accompanied by slower production of muscle differentiation markers. To identify the mechanisms through which FUS inhibits myogenesis, we uncovered RNA targets of FUS by ribonucleoprotein immunoprecipitation (RIP) followed by RNA-sequencing (RNA-seq) analysis. Stringent selection of the bound transcripts uncovered Tnnt1 mRNA, encoding troponin T (TNNT1), as a major effector of FUS influence on myogenesis. We found that in myoblasts, FUS sequestered Tnnt1 mRNA in the nucleus, preventing TNNT1 expression; however, reduction of FUS during myogenesis or by silencing FUS released Tnnt1 mRNA for export to the cytoplasm, where it accumulated and was translated into TNNT1, promoting myogenesis. We propose that FUS inhibits myogenesis by suppressing TNNT1 expression through a mechanism of nuclear mRNA retention.

2024-09-13 | GSE267276 | GEO

Novel RNA-binding activity of MYF5 enhances Ccnd1/Cyclin D1 mRNA translation during myogenesis

Project description:Skeletal muscle contains long multinucleated and contractile structures known as muscle fibers, which arise from the fusion of myoblasts into nucleated myotubes during myogenesis. The myogenic regulatory factor (MRF) MYF5 is the earliest to be expressed during myogenesis and functions as a transcription factor in muscle progenitor cells (satellite cells) and myocytes. In mouse C2C12 myocytes, MYF5 is implicated in the initial steps of myoblast differentiation into myotubes. Ribonucleoprotein immunoprecipitation (RIP) analysis showed that MYF5 bound a subset of myoblast mRNAs; prominent among them was Ccnd1 mRNA, which encodes the key cell cycle regulator CCND1 (Cyclin D1). Biotin-RNA pulldown, UV-crosslinking, and gel shift experiments indicated that MYF5 was capable of binding the 3' untranslated region (UTR) and the coding region (CR) of Ccnd1 mRNA. MYF5 silencing in proliferating growing myoblasts revealed that and MYF5 promoted CCND1 translation, and it also modestly increased transcription of Ccnd1 mRNA. Importantly, silencing MYF5 reduced myoblast growth as well as differentiation of myoblasts into myotubes, while overexpressing MYF5 in C2C12 cells upregulated CCND1 expression. We propose that MYF5 enhances early myogenesis in part by coordinately elevating Ccnd1 transcription and Ccnd1 mRNA translation. Four replicates were utilized from either Control (IgG) or MYF5-immunoprecipitated RNA samples from C2C12 cells growing in either growth medium (GM) or differentiation medium (DM) for a total of sixteen samples.

2016-08-08 | E-GEOD-73704 | biostudies-arrayexpress

Novel RNA-binding activity of MYF5 enhances Ccnd1/Cyclin D1 mRNA translation during myogenesis

2016-08-08 | GSE73704 | GEO

An Evolutionarily-Conserved Long Noncoding RNA Myolinc Regulates muscle differentiation [array_knockdown]

Project description:Myogenesis is a complex process required for skeletal muscle formation during embryonic development and for regeneration and growth of myofibers in adults. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) play key roles in regulating cell fate decision and function in various tissues. However, the role of lncRNAs in the regulation of myogenesis remains poorly understood. In this study, we identified a novel muscle-enriched lncRNA called "Myolinc (AK142388)", which we functionally characterized in the C2C12 myoblast cell line. Myolinc is predominately localized in the nucleus, and its levels increase upon induction of the differentiation. Knockdown of Myolinc impairs the expression of myogenic regulatory factors and formation of multinucleated myotubes in cultured myoblasts. Myolinc also regulates the expression of Filip1 in a cis-manner. Similar to Myolinc, knockdown of Filip1 inhibits myogenic differentiation. Furthermore, Myolinc binds to TAR DNA-binding protein 43 (TDP-43), a DNA/RNA-binding protein that regulates the expression of muscle genes (e.g. Acta1 and MyoD). Knockdown of TDP-43 inhibits myogenic differentiation. We also show that Myolinc-TDP-43 interaction is essential for the binding of TDP-43 to the promoter regions of muscle marker genes. Finally, we show that silencing of Myolinc inhibits skeletal muscle regeneration in adult mice. Altogether, our study identifies a novel lncRNA that controls key regulatory networks of myogenesis.

2018-04-06 | GSE69451 | GEO

An Evolutionarily-Conserved Long Noncoding RNA Myolinc Regulates muscle differentiation [ChIP-seq]

2018-04-06 | GSE69527 | GEO

An Evolutionarily-Conserved Long Noncoding RNA Myolinc Regulates muscle differentiation [array_overexpression]

2018-04-06 | GSE69455 | GEO

ADAMTSL2 regulates Wnt signaling in myogenesis

Project description:ADAMTSL2 mutations cause geleophysic dysplasia, which is characterized by short stature, pseudomuscular build, joint stiffness and tight skin. To elucidate the role of ADAMTSL2 in skeletal muscle myogenesis, we used C2C12 myoblasts, which differentiate and form myotubes when serum is reduced as a model system for myogenesis. Adamtsl2 was depleted by stably expressing shRNA targeting Adamtsl2 mRNA. Upon shRNA-mediated depletion of Adamtsl2, C2C12 myoblasts did not differentiate and did not form myosin heavy chain-positive myotubes in cell culture.

2021-10-16 | GSE185894 | GEO

Comprehensive analysis of the proteome, phosphoproteome and N-linked sialylated glycoproteome of C2C12 myoblasts

Project description:C2C12 myoblast is a model that has been used extensively to study the process of skeletal muscle differentiation. Proteomics has advanced our understanding of skeletal muscle biology and the process of myogenesis. However, there is still no deep coverage of C2C12 myoblast proteome, which is important for the understanding of key drivers for the differentiation of skeletal muscle cells. Here, we conducted a multi-dimensional proteome profiling with TiSH strategy to get a comprehensive analysis of proteome, phosphoproteome and N-linked sialylated glycoproteome of C2C12 myoblasts. A total of 8313 protein groups were identified in C2C12 myoblasts, including 7827 protein groups from non-modified peptides, 3803 phosphoproteins and 977 formerly N-linked sialylated glycoproteins.

2020-11-27 | PXD011334 | Pride

HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA (miRNA)

Project description:Upon muscle injury the high mobility group box 1 (HMGB1) protein is up-regulated and secreted to initiate reparative responses. Here we show that HMGB1 controls myogenesis both in vitro and in vivo, during development and after adult muscle injury. HMGB1 expression in muscle cells is regulated at the translational level: the miRNA miR-1192 inhibits HMGB1 translation and the RNA-binding protein HuR promotes it. HuR binds to a cis-element, HuRBS, located in the 3'UTR of the HMGB1 transcript, and at the same time miR-1192 is recruited to an adjacent seed element. The binding of HuR to the HuRBS prevents the recruitment of Argonaute 2 (Ago2), overriding miR-1192-mediated translation inhibition. Depleting HuR reduces myoblast fusion and silencing miR-1192 re-establishes the fusion potential of HuR-depleted cells. We propose that HuR promotes the commitment of myoblasts to myogenesis by enhancing the translation of HMGB1 and suppressing the translation inhibition mediated by miR-1192. RNA content was extracted following immunoprecipitation of HuR using a monoclonal antibody (3A2) and the levels of mRNA were compared to an IgG control in order to determine which transcripts were enriched in the HuR ribonucleoprotein complex.

2013-08-14 | E-GEOD-49855 | biostudies-arrayexpress

HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA (mRNA)

2013-08-14 | E-GEOD-49856 | biostudies-arrayexpress

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