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Lnc-mg is a long non-coding RNA that promotes myogenesis [miRNA Array]

ABSTRACT: Recent studies have indicated important roles for long noncoding RNAs (lncRNAs) as potential essential regulators of myogenesis and adult skeletal muscle regeneration. However, in vivo, the role and mechanism of lncRNAs in myogenic differentiation of adult skeletal muscle stem cells (MuSCs) and myogenesis are still largely unknown. Here, we identified a skeletal muscle specific-enriched lncRNA (myogenesis-associated lncRNA, short for lnc-mg). In vivo, skeletal muscle conditional knockout of lnc-mg resulted in muscle atrophy and the loss of muscular endurance during exercise. Alternatively, skeletal muscle-specific overexpression of lnc-mg promoted muscle hypertrophy in mice. In vitro analyses of primary skeletal muscle cells isolated from mice showed that expression of lnc-mg was increased gradually during myogenic differentiation and overexpressed lnc-mg improved cell differentiation. Mechanistically, lnc-mg promoted myogenesis, by functioning as a competing endogenous RNA (ceRNA) for miR-125b to control protein abundance of Igf2. These findings identify lnc-mg as a novel and important noncoding regulator for muscle cell differentiation and skeletal muscle development. In order to test the hypothesis that lnc-mg may function as a ceRNA leading to the liberation of corresponding miRNA-targeted transcripts, microarrays were performed to detect miRNAs expression in lnc-mg overexpression and lnc-mg knockdown C2C12 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE93277 | GEO | 2017/03/01

SECONDARY ACCESSION(S): PRJNA360456

REPOSITORIES: GEO

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lnc-mg is a long non-coding RNA that promotes myogenesis [lncRNA]

Project description:Recent studies have indicated important roles for long noncoding RNAs (lncRNAs) as potential essential regulators of myogenesis and adult skeletal muscle regeneration. However, in vivo, the role and mechanism of lncRNAs in myogenic differentiation of adult skeletal muscle stem cells (MuSCs) and myogenesis are still largely unknown. Here, we identified a skeletal muscle specific-enriched lncRNA (myogenesis-associated lncRNA, short for lnc-mg). In vivo, skeletal muscle conditional knockout of lnc-mg resulted in muscle atrophy and the loss of muscular endurance during exercise. Alternatively, skeletal muscle-specific overexpression of lnc-mg promoted muscle hypertrophy in mice. In vitro analyses of primary skeletal muscle cells isolated from mice showed that expression of lnc-mg was increased gradually during myogenic differentiation and overexpressed lnc-mg improved cell differentiation. Mechanistically, lnc-mg promoted myogenesis, by functioning as a competing endogenous RNA (ceRNA) for miR-125b to control protein abundance of Igf2. These findings identify lnc-mg as a novel and important noncoding regulator for muscle cell differentiation and skeletal muscle development. In order to identify functional lncRNAs correlating with myogenesis, microarrays were performed to detect the lncRNAs expression profile in undifferentiated MuSCs (GM, growth media/GM) ) and differentiated MuSCs (DM, differentiation media/DM).

2017-03-01 | GSE93276 | GEO

Muscle stems cell LC-MS - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

Project description:Abstract Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed Taz in vivo and ex vivo in comparison to Yap. Taz was expressed in activated satellite cells. siRNA knockdown or constitutive expression of wildtype or constitutively active TAZ mutants showed that TAZ promoted proliferation, a function that was shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene symbol Wwtr1-/-) knockout mice, there were no overt effect on regeneration. However, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapflox/flox : Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common Taz/Yap targets, but Taz also regulates some genes independently of Yap, including myogenic genes such as Pax7, Myf5 and Myod1. Proteomic analysis of Yap/Taz revealed many common binding partners, but Taz also interacts with proteins distinct from Yap, that are mainly involved in myogenesis and aspects of cytoskeleton organization. Neither TAZ nor YAP bind members of the Wnt destruction complex but both extensively changed expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to promote myogenic differentiation.

2017-06-13 | PXD005751 | Pride

Human myogenesis is driven by proline-directed kinases and the trans-histone code, H3K9me3/H4K20me3

Project description:System-level analysis of the (phospho)proteome during muscle formation and its interplay with epigenetic factors is critical to understand muscular diseases. Using stable isotope labeling (SILAC) and nano liquid chromatography-tandem mass spectrometry (nLC-MS/MS), we analyzed the (phospho)proteome during myogenesis of LHCN-M2 human skeletal myoblast cell line. First, enriched phosphorylation motifs suggested that PKC, cyclin-dependent kinase and MAPK are regulatory kinases during myodifferentiation. Then, we uncovered that the drugs known to inhibit these kinases either promoted myogenesis (PD0325901 and GW8510) or stall differentiation (CHIR99021 and roscovitine). We identified differentiation-specific myogenic and chromatin-related proteins, including histone methyltransferases. We then analyzed histone post-translational modifications (PTMs), and observed regulation of two gene-silencing marks, H3K9me3 and H4K20me3, in a correlated manner with the observed phenotypes. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) confirmed that H3K9me3 is erased from the myogenic regulatory factors (MRFs) MyoD, MyoG and Myf5 in differentiating myotubes. Together, our work demonstrates that the integration of histone PTM, phosphoproteomics and full proteome analysis gives a comprehensive understanding of the close connection between signaling pathways and epigenetics during differentiation of myotube in vitro.

2019-03-14 | PXD007589 | Pride

Single Cell sequencing of mononuclear cells from regenerating skeletal muscle

Project description:Skeletal muscle stem cells, or satellite cells (SCs), are essential to regenerate and maintain muscle. Quiescent SCs reside in an asymmetric niche between the basal lamina and myofiber membrane. To repair muscle, SCs activate, proliferate, and differentiate, fusing to repair myofibers or reacquiring quiescence to replenish the SC niche. Little is known about when SCs reacquire quiescence during regeneration or the cellular processes that direct SC fate decisions and progression through myogenesis. Single cell sequencing of myogenic cells in regenerating muscle identifies SCs reacquiring quiescence and reveals that non-cell autonomous signaling networks influence SC fate decisions during regeneration. Single cell RNA-sequencing of regenerating skeletal muscle reveals that RBP expression, including numerous neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates to stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discover that the neuromuscular disease associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis controlling myogenic cell fate transitions during terminal differentiation.

2022-06-11 | GSE205690 | GEO

RNA-binding protein AUF1 promotes myogenesis by regulating MEF2C expression levels

Project description:The mammalian RNA-binding protein AUF1 (AU-binding factor 1, also known as heterogeneous nuclear ribonucleoprotein D, hnRNP D) binds to numerous mRNAs and influences their post-transcriptional fate. Given that many AUF1 target mRNAs encode muscle-specific factors, we investigated the function of AUF1 in skeletal muscle differentiation. In mouse C2C12 myocytes, where AUF1 levels rise at the onset of myogenesis and remain elevated throughout myocyte differentiation into myotubes, RIP (RNP immunoprecipitation) analysis indicated that AUF1 binds prominently to Mef2c (myocyte enhancer factor 2c) mRNA, which encodes the key myogenic transcription factor Mef2c. By performing mRNA half-life measurements and polysome distribution analysis, we found that AUF1 associated with the 3’UTR of Mef2c mRNA and promoted Mef2c translation without affecting Mef2c mRNA stability. In addition, AUF1 promoted Mef2c gene transcription via a lesser-known role of AUF1 in transcriptional regulation. Importantly, lowering AUF1 delayed myogenesis, while ectopically restoring Mef2c expression levels partially rescued the impairment of myogenesis seen after reducing AUF1 levels. We propose that Mef2c is a key effector of the myogenesis program promoted by AUF1. Keywords: ribonucleoprotein complex; post-transcriptional gene regulation; muscle cell differentiation; myocytes; mRNA translation; mRNA stability; post-transcriptional gene regulation; transcriptome

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Single Cell RNA-Sequencing of Human Limb Skeletal Muscle across Development and Myogenic Culture from Pluripotent Stem Cells

Project description:The developmental trajectory of human skeletal myogenesis and the transition between progenitor and stem cell states are unclear. To address this, we employed single cell RNA-sequencing to profile human skeletal muscle tissues from embryonic, fetal and postnatal stages. In silico, we identified myogenic as well as other cell types and constructed a “roadmap” of human skeletal muscle ontogeny across development. In a similar fashion, we also profiled the heterogeneous cell cultures generated from multiple human pluripotent stem cell (hPSC) myogenic differentiation protocols, and mapped hPSC-derived myogenic progenitors to an embryonic-to-fetal transition period. Additionally, we found differentially enriched biological processes and discovered co-regulated gene networks and transcription factors present at distinct myogenic stages. In summary, this work serves as a resource for advancing our knowledge of human myogenesis. It also provides a tool for better characterization and understanding of hPSC-derived myogenic progenitors for translational applications in skeletal muscle based regenerative medicine.

2020-04-29 | GSE147457 | GEO

Long non-coding RNA Linc-RAM enhances myogenic differentiation by interacting with MyoD

Project description:Long non-coding RNAs are important regulators of diverse biological prosesses. Here, we report on functional identification and characterization of a novel long intergenic noncoding RNA with MyoD-regulated and skeletal muscle-restricted expression that promotes the activation of the myogenic program, and is therefore termed Linc-RAM (Linc-RNA Activator of Myogenesis). Linc-RAM is transcribed from an intergenic region of myogenic cells and its expression is upregulated during myogenesis. Notably, in vivo functional studies show that Linc-RAM knockout mice display impaired muscle regeneration due to differentiation defect of satellite cells. Mechanistically, Linc-RAM regulates expression of myogenic genes by directly binding MyoD, which in turn promotes the assembly of the MyoD-Baf60c-Brg1 complex on the regulatory elements of target genes. Collectively, our findings reveal the functional role and molecular mechanism of a lineage-specific Linc-RAM as a regulatory lncRNA required for tissues-specific chromatin remodeling and gene expression.

2016-12-25 | GSE72601 | 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

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Project description:Long noncoding RNAs (lncRNAs) are involved in the regulation of skeletal muscle development. In the present study, differentially expressed lncRNAs were identified from RNA-seq data derived from myoblasts and myotubes. We conducted studies to elucidate the function and molecular mechanism of action of Linc-smad7 during skeletal muscle development. Our findings show that Linc-smad7 is upregulated during the early phase of myoblasts differentiation. In in vitro studies, we showed that overexpression of Linc-smad7 promoted the arrest of myoblasts in G1 phase, inhibited DNA replication, and induced myoblast differentiation. Our in vivo studies suggest that Linc-smad7 stimulates skeletal muscle regeneration in cardiotoxin-induced muscle injury. Mechanistically, Linc-smad7 overexpression increased smad7 and IGF2 protein levels. On the contrary, overexpression of miR-125b reduced smad7 and IGF2 protein levels. Results of RNA immunoprecipitation analysis and biotin-labeled miR-125b capture suggest that Linc-smad7 could act as a competing endogenous RNA (ceRNA) for miRNA-125b. Taken together, our findings suggest that the novel noncoding regulator Linc-smad7 regulates skeletal muscle development.

2017-11-01 | GSE106365 | GEO

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

Project description:Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we find that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX, which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin like-growth factor-2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned media from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is conserved in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling.â??The data pproided are histome H4 acetlation data for MLX DN and MLX wt samples; 3 MLX DN H4 Ac Chip seq samples , 3 Inputs, 3 MLX WT H4 Ac samples and 3 WT inputs

2015-11-11 | E-GEOD-74678 | biostudies-arrayexpress

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