Myh7b/miR-499 gene expression is transcriptionally regulated by MRFs and Eos

Yeung, Fan; Chung, Eunhee; Guess, Martin G.; Bell, Matthew L.; Leinwand, Leslie A.

doi:10.1093/nar/gks466

Cited by 33 publications

(25 citation statements)

References 32 publications

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“…Interestingly, in addition to lack of exercise influence over mir-499 quantities, we noted that this particular microRNA expresses in very low amounts in both the groups further downgrading its ability to mediate any physiological responses in skeletal muscles. In addition mir-499 expression might have very well diminished in differentiated matured muscles, as its expression is regulated by the myogenic transcriptional factors such as MyoD [50], suggesting its limited role during the muscle differentiation phase.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications

Veeranki

Winchester

Tyagi

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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HHcy has been implicated in elderly frailty, but the underlying mechanisms are poorly understood. Using C57 and CBS+/- mice and C2C12 cell line, we investigated mechanisms behind HHcy induced skeletal muscle weakness and fatigability. Possible alterations in metabolic capacity (levels of LDH, CS, MM-CK and COX-IV), in structural proteins (levels of dystrophin) and in mitochondrial function (ATP production) were examined. An exercise regimen was employed to reverse HHcy induced changes. CBS+/- mice exhibited more fatigability, and generated less contraction force. No significant changes in muscle morphology were observed. However, there is corresponding reduction in large muscle fiber number in CBS+/- mice. Excess fatigability was not due to changes in key enzymes involved in metabolism, but was due to reduced ATP levels. A marginal reduction in dystrophin levels along with a decrease in mitochondrial transcription factor A (mtTFA) were observed. There was also an increase in the mir-31, and mir-494 quantities that were implicated in dystrophin and mtTFA regulation respectively. The molecular changes elevated during HHcy, with the exception of dystrophin levels, were reversed after exercise. In addition, amount of NRF-1, one of the transcriptional regulators of mtTFA, was significantly decreased. Furthermore, there was enhancement in mir-494 levels and a concomitant decline in mtTFA protein quantity in homocysteine treated cells. These changes in C2C12 cells were also accompanied by an increase in DNMT3a and DNMT3b proteins and global DNA methylation levels. Together, these results suggest that HHcy plays a causal role in enhanced fatigability through mitochondrial dysfunction which involves epigenetic changes.

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Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications

Veeranki

Winchester

Tyagi

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The spatio-temporal expression of the major skeletal MYHs in teleost fish is regulated by small regions scattered throughout the 5′-flanking sequence [18,30,34,35]. Recently, Yeung et al [36] reported promoter activity in a 6.2-kb upstream sequence of mouse MYH14 that mimics endogenous MYH14 and miR-499 expression. Therefore, these conserved regions in the 5′-flanking sequence may act as a promoter for the spatio-temporal expression of MYH14 , and the regulatory sequences are conserved in medaka miR-499 despite the loss of the MYH14 gene.…”

Section: Discussionmentioning

confidence: 99%

Evolution of the myosin heavy chain gene MYH14 and its intronic microRNA miR-499: muscle-specific miR-499 expression persists in the absence of the ancestral host gene

et al. 2013

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BackgroundA novel sarcomeric myosin heavy chain gene, MYH14, was identified following the completion of the human genome project. MYH14 contains an intronic microRNA, miR-499, which is expressed in a slow/cardiac muscle specific manner along with its host gene; it plays a key role in muscle fiber-type specification in mammals. Interestingly, teleost fish genomes contain multiple MYH14 and miR-499 paralogs. However, the evolutionary history of MYH14 and miR-499 has not been studied in detail. In the present study, we identified MYH14/miR-499 loci on various teleost fish genomes and examined their evolutionary history by sequence and expression analyses.ResultsSynteny and phylogenetic analyses depict the evolutionary history of MYH14/miR-499 loci where teleost specific duplication and several subsequent rounds of species-specific gene loss events took place. Interestingly, miR-499 was not located in the MYH14 introns of certain teleost fish. An MYH14 paralog, lacking miR-499, exhibited an accelerated rate of evolution compared with those containing miR-499, suggesting a putative functional relationship between MYH14 and miR-499. In medaka, Oryzias latipes, miR-499 is present where MYH14 is completely absent in the genome. Furthermore, by using in situ hybridization and small RNA sequencing, miR-499 was expressed in the notochord at the medaka embryonic stage and slow/cardiac muscle at the larval and adult stages. Comparing the flanking sequences of MYH14/miR-499 loci between torafugu Takifugu rubripes, zebrafish Danio rerio, and medaka revealed some highly conserved regions, suggesting that cis-regulatory elements have been functionally conserved in medaka miR-499 despite the loss of its host gene.ConclusionsThis study reveals the evolutionary history of the MYH14/miRNA-499 locus in teleost fish, indicating divergent distribution and expression of MYH14 and miR-499 genes in different teleost fish lineages. We also found that medaka miR-499 was even expressed in the absence of its host gene. To our knowledge, this is the first report that shows the conversion of intronic into non-intronic miRNA during the evolution of a teleost fish lineage.

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“…The presence of binding sites for myogenic transcription factors in miRNA promoters, as well as the locations of some miRNA loci within introns of myogenic genes, result in highly regulated expression. For example, myogenic transcription factors that are known drivers of skeletal muscle specification and differentiation, including MyoD, myogenin and MYF5, bind to and activate the promoters of miR-206, miR-486 and miR-499 and the bicistronic miRNAs miR-1 and miR-133 (REFS 14–18) (FIG. 3a).…”

Section: Mirnas In Myogenesismentioning

confidence: 99%

Regulation of microRNA function in somatic stem cell proliferation and differentiation

Shenoy

Blelloch

2014

Nat Rev Mol Cell Biol

323

234

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microRNAs (miRNAs) are important modulators of development. Owing to their ability to simultaneously silence hundreds of target genes, they have key roles in large-scale transcriptomic changes that occur during cell fate transitions. In somatic stem and progenitor cells — such as those involved in myogenesis, haematopoiesis, skin and neural development — miRNA function is carefully regulated to promote and stabilize cell fate choice. miRNAs are integrated within networks that form both positive and negative feedback loops. Their function is regulated at multiple levels, including transcription, biogenesis, stability, availability and/or number of target sites, as well as their cooperation with other miRNAs and RNA-binding proteins. Together, these regulatory mechanisms result in a refined molecular response that enables proper cellular differentiation and function.

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Myh7b/miR-499 gene expression is transcriptionally regulated by MRFs and Eos

Cited by 33 publications

References 32 publications

Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications

Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications

Evolution of the myosin heavy chain gene MYH14 and its intronic microRNA miR-499: muscle-specific miR-499 expression persists in the absence of the ancestral host gene

Regulation of microRNA function in somatic stem cell proliferation and differentiation

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