An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133

Departments of Molecular Biology and Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(52):20844-9. DOI: 10.1073/pnas.0710558105
Source: PubMed


The muscle-specific microRNAs, miR-1 and miR-133, play important roles in muscle growth and differentiation. Here, we show that the MEF2 transcription factor, an essential regulator of muscle development, directly activates transcription of a bicistronic primary transcript encoding miR-1-2 and 133a-1 via an intragenic muscle-specific enhancer located between the miR-1-2 and 133a-1 coding regions. This MEF2-dependent enhancer is activated in the linear heart tube during mouse embryogenesis and thereafter controls transcription throughout the atrial and ventricular chambers of the heart. MEF2 together with MyoD also regulates the miR-1-2/-133a-1 intragenic enhancer in the somite myotomes and in all skeletal muscle fibers during embryogenesis and adulthood. A similar muscle-specific intragenic enhancer controls transcription of the miR-1-1/-133a-2 locus. These findings reveal a common architecture of regulatory elements associated with the miR-1/-133 genes and underscore the central role of MEF2 as a regulator of the transcriptional and posttranscriptional pathways that control cardiac and skeletal muscle development.

    • "The expression of the four myomiRs is induced during muscle cell differentiation, indicating that they have a crucial role in regulating the process (Chen et al., 2006; Kim et al., 2006). Their expression is regulated by the MRFs MyoD and myogenin, as well as serum response factor (SRF) and myocyte enhancer factor 2 (MEF2) (Chen et al., 2006; Rao et al., 2006; Liu et al., 2007). MyomiR levels are found to be increased during the late stages of human foetal muscle development, and increases in their expression levels are proportional to the capacity of myoblasts to form myotubes (Koutsoulidou et al., 2011b). "
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    ABSTRACT: Twist-1 is mostly expressed during development and has been previously shown to control myogenesis. Since its regulation in muscle has not been fully exploited, the aim of the project was to identify miRNAs in muscle which regulate Twist-1. miR-206, one of the most important myomiRs, was identified as a possible candidate for Twist-1 mRNA. Luciferase assays and transfections in human foetal myoblasts showed that Twist-1 is a direct target for miR-206 and through this pathway muscle cell differentiation is promoted. We next investigated whether MyoD, a major myogenic transcription factor regulates Twist-1, since it is known that MyoD induces miR-206 gene expression. We found that forced MyoD expression induces miR-206 up-regulation and Twist-1 down-regulation through miR-206 promoter binding, followed by increase in muscle cell differentiation. Finally, experiments were performed in muscle cells from patients with congenital Myotonic Dystrophy type 1 which fail to differentiate to myotubes. MyoD overexpression inhibited Twist-1 through miR-206 induction, followed by an increase in muscle cell differentiation. These results reveal a novel mechanism of myogenesis which might also play an important role in muscle disease. © 2015. Published by The Company of Biologists Ltd.
    No preview · Article · Aug 2015 · Journal of Cell Science
    • "Individual microRNAs can target dozens of mRNAs, often with similar biological function. In skeletal muscle, the MyoD, MEF2, and SRF families of transcription factors cooperatively regulate the expression of two microRNA clusters, encoding miR-1 and miR-133a (Chen et al. 2006; Liu et al. 2007) (Fig. 2). The miR- 133a knock-out mice develop a myopathy that is accompanied by impaired lipid metabolism and mitochondrial respiration (Liu et al. 2011). "
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    ABSTRACT: The prevalence of type 2 diabetes (T2D) has increased dramatically over the past two decades, not only among adults but also among adolescents. T2D is a systemic disorder affecting every organ system and is especially damaging to the cardiovascular system, predisposing individuals to severe cardiac and vascular complications. The precise mechanisms that cause T2D are an area of active research. Most current theories suggest that the process begins with peripheral insulin resistance that precedes failure of the pancreatic β-cells to secrete sufficient insulin to maintain normoglycemia. A growing body of literature has highlighted multiple aspects of mitochondrial function, including oxidative phosphorylation, lipid homeostasis, and mitochondrial quality control in the regulation of peripheral insulin sensitivity. Whether the cellular mechanisms of insulin resistance in adults are comparable to that in adolescents remains unclear. This review will summarize both clinical and basic studies that shed light on how alterations in skeletal muscle mitochondrial function contribute to whole body insulin resistance and will discuss the evidence supporting high-intensity exercise training as a therapy to circumvent skeletal muscle mitochondrial dysfunction to restore insulin sensitivity in both adults and adolescents.
    No preview · Article · May 2015 · Biochemistry and Cell Biology
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    • "It has been reported that miR-1-1/133a2 and miR-1-2/133a1 are transcribed as bicistronic transcripts on different chromosomes (Fig. 2 A; Liu et al., 2007). To further study the regulation of miR-133a by TH, miR-1-2/133a1 and miR-1-1/133a2 enhancers were cloned. "
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    ABSTRACT: It is known that thyroid hormone (TH) is a major determinant of muscle fiber composition, but the molecular mechanism by which it does so remains unclear. Here, we demonstrated that miR-133a1 is a direct target gene of TH in muscle. Intriguingly, miR-133a, which is enriched in fast-twitch muscle, regulates slow-to-fast muscle fiber type conversion by targeting TEA domain family member 1 (TEAD1), a key regulator of slow muscle gene expression. Inhibition of miR-133a in vivo abrogated TH action on muscle fiber type conversion. Moreover, TEAD1 overexpression antagonized the effect of miR-133a as well as TH on muscle fiber type switch. Additionally, we demonstrate that TH negatively regulates the transcription of myosin heavy chain I indirectly via miR-133a/TEAD1. Collectively, we propose that TH inhibits the slow muscle phenotype through a novel epigenetic mechanism involving repression of TEAD1 expression via targeting by miR-133a1. This identification of a TH-regulated microRNA therefore sheds new light on how TH achieves its diverse biological activities. © 2014 Zhang et al.
    Full-text · Article · Dec 2014 · The Journal of Cell Biology
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