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

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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    • "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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    Biochemistry and Cell Biology 05/2015; DOI:10.1139/bcb-2015-0012 · 2.15 Impact Factor
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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; 207(6). DOI:10.1083/jcb.201406068 · 9.83 Impact Factor
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    • "The two most abundant miRNAs in our data, miR-206 and miR-1, together account for 36% of the total known miRNAs (Figure 2). Their role in skeletogenesis and myogenesis has been studied in some detail, for example miR-206 has been found to induce myogenic differentiation [65]–[67] while inhibiting osteoblast differentiation [68], and miR-1 has been found to regulate skeletal muscle and cardiac development [69], [70]. These miRNAs are highly conserved in animal evolution [8] with miR-1 retaining its muscle-specific expression from C. elegans to human [71]. "
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    ABSTRACT: Micro-RNAs (miRNAs) are now recognized as a major class of developmental regulators. Sequences of many miRNAs are highly conserved, yet they often exhibit temporal and spatial heterogeneity in expression among species and have been proposed as an important reservoir for adaptive evolution and divergence. With this in mind we studied miRNA expression during embryonic development of offspring from two contrasting morphs of the highly polymorphic salmonid Arctic charr (Salvelinus alpinus), a small benthic morph from Lake Thingvallavatn (SB) and an aquaculture stock (AC). These morphs differ extensively in morphology and adult body size. We established offspring groups of the two morphs and sampled at several time points during development. Four time points (3 embryonic and one just before first feeding) were selected for high-throughput small-RNA sequencing. We identified a total of 326 conserved and 427 novel miRNA candidates in Arctic charr, of which 51 conserved and 6 novel miRNA candidates were differentially expressed among developmental stages. Furthermore, 53 known and 19 novel miRNAs showed significantly different levels of expression in the two contrasting morphs. Hierarchical clustering of the 53 conserved miRNAs revealed that the expression differences are confined to the embryonic stages, where miRNAs such as sal-miR-130, 30, 451, 133, 26 and 199a were highly expressed in AC, whereas sal-miR-146, 183, 206 and 196a were highly expressed in SB embryos. The majority of these miRNAs have previously been found to be involved in key developmental processes in other species such as development of brain and sensory epithelia, skeletogenesis and myogenesis. Four of the novel miRNA candidates were only detected in either AC or SB. miRNA candidates identified in this study will be combined with available mRNA expression data to identify potential targets and involvement in developmental regulation.
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