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: 9.81). 01/2008; 104(52):20844-9. DOI: 10.1073/pnas.0710558105
Source: PubMed

ABSTRACT 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.

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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.
    The Journal of Cell Biology 12/2014; DOI:10.1083/jcb.201406068 · 9.69 Impact Factor
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    • "Thus, the regulation of these muscle-specific miRNAs as well as their relationship with muscle functions such as myogenesis , hypertrophy, and energy metabolism, has been of particular interest. Expression of muscle-specific proteins/miRNAs is regulated by key myogenic regulatory factors (MRFs), myocyte enhancer factor 2 (MEF2), serum response factor (SRF), and myocardinrelated transcription factor-A (Chen et al., 2006; Rao et al., 2006; Rosenberg et al., 2006; Liu et al., 2007; Small et al., 2010). "
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. Recently, growing evidence has shown that miRNAs are taken in by intracellular exosomes, secreted into circulation, and taken up by other cells. Circulating levels of several miRNAs are changed in diseases such as cancer, diabetes, and cardiovascular diseases; therefore, they are suggested to regulate functions of the recipient cells by modulating protein expression. Circulating miRNAs (c-miRNAs) may also modulate skeletal muscle function in physiological and pathological conditions. It has been suggested that acute and chronic exercise transiently or adaptively changes the level of c-miRNAs, thus post-transcriptionally regulating proteins associated with energy metabolism, myogenesis, and angiogenesis. Circulating levels of several miRNAs that are enriched in muscle are altered in muscle disorders and may be involved in their development and progression. In addition, such c-miRNAs may be useful as biomarkers to determine various interactions between tissues and also to reflect athletic performance, physical fatigue, incidence risk, and development of diseases.
    Frontiers in Physiology 02/2014; 5:39. DOI:10.3389/fphys.2014.00039 · 3.50 Impact Factor
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    • "The enhancer regions of this locus contains a conserved MEF2-like site (CTATTTTAG), a MyoD-binding E-box (CANNTG) [22] and YY1 [20] (Fig. 3A). It was demonstrated that a CArG box (CC(A/T)6GG) is in the enhancer region of miR-133a-2 [23], but not in the enhancer region of miR-133a-1. "
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    ABSTRACT: Reversine has been shown to induce dedifferentiation of C2C12 murine myoblasts into multipotent progenitor cells. However, little is known about the key regulators mediating the dedifferentiation induced by reversine. Here, we show that large scale miRNA gene expression profiling of reversine-treated C2C12 myoblasts identifies a down-regulated miRNA, miR-133a, involved in dedifferentiation of myoblasts. Reversine treatment results in up- and down-regulated miRNA profiles. Among miRNAs affected by reversine, the level of muscle-specific miR-133a, which has been shown to be up-regulated during muscle development and to suppress differentiation into other lineages, is markedly reduced by treatment of C2C12 myoblasts with reversine. In parallel, reversine decreases the expression and recruitment of myogenic factor, SRF, to the enhancer regions of miR-133a. Sequentially, down-regulation of miR-133a by reversine is accompanied by a decrease in active histone modifications including trimethylation of histone H3K4 and H3K36, phosphorylation of H3S10, and acetylation of H3K14 on the miR-133a promoter, leading to dissociation of RNA polymerase II from the promoter. Furthermore, inhibition of miR-133a by transfection of C2C12 myoblasts with miR-133a inhibitor increases the expression of osteogenic lineage marker, Ogn, and adipotenic lineage marker, ApoE, similar to that in response to reversine. In contrast, the co-overexpression of miR-133a mimic reversed the effect of reversine on C2C12 myoblast dedifferentiation. Taken together, the results indicate that reversine induces a multipotency of C2C12 myoblasts by suppression of miR-133a expression through depletion of active histone modifications, and suggest that miR-133a is a potential miRNA regulating the reversine-induced dedifferentiation. Collectively, our findings provide a mechanistic rationale for the application of reversine to dedifferentiation of somatic cells.
    Biochemical and Biophysical Research Communications 02/2014; 445(1). DOI:10.1016/j.bbrc.2014.02.002 · 2.28 Impact Factor
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