Sp3 Proteins Negatively Regulate β Myosin Heavy Chain Gene Expression during Skeletal Muscle Inactivity

Tsika, Gretchen L.; Ji, Juan; Tsika, R. W.

doi:10.1128/mcb.24.24.10777-10791.2004

Cited by 23 publications

(24 citation statements)

References 53 publications

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“…Targeting of Sox6, Thrap1, myostatin, Mapk6, and Sp3 suggests that miR-499 could influence muscle fiber type by finetuning the expression of genes that influence muscle development and fiber type specification (11,14,26,38,39).…”

Section: Discussionmentioning

confidence: 99%

Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping

Bell

Buvoli

Leinwand

2010

Molecular and Cellular Biology

122

138

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The ancient MYH7b gene, expressed in striated muscle and brain, encodes a sarcomeric myosin and the intronic microRNA miR-499. We find that skipping of an exon introduces a premature termination codon in the transcript that downregulates MYH7b protein production without affecting microRNA expression. Among other genes, endogenous miR-499 targets the 3 untranslated region of the transcription factor Sox6, which in turn acts as a repressor of MYH7b transcriptional activity. Thus, concerted transcription and alternative splicing uncouple the level of expression of MYH7b and miR-499 when their coexpression is not required.Skeletal and cardiac muscle exhibit a broad range of contractile characteristics and adaptive responses that are controlled, at least in part, by sarcomeric myosins, a multigene family of actin-based motors that convert chemical energy released from ATP hydrolysis into mechanical force. In addition to the eight well-characterized myosin heavy chain (MYH) isoforms expressed in heart and skeletal muscle, three more ancient myosin genes, MYH7b (MYH14), MYH15, and MYH16, have been identified (13). In humans, the MYH16 gene is a pseudogene by virtue of a frameshift mutation and consequent premature termination codon (PTC). Remarkably, the gene is not mutated in other nonhuman primates and appears to regulate the fiber size of the masticatory muscles (35). Phylogenetic analysis suggests that MYH7b is most closely related to ␣-and ␤-cardiac myosins, with 69% amino acid identity. Moreover, these three related myosin genes encode microRNAs (miRNAs) in one of their introns (MYH-␣, miR-208a; MYH-␤, miR-208b; and MYH7b, miR-499) (40, 41). In particular, miR-208a has been shown to be a key mediator of the stress response and a regulator of hypertrophy and electrical conduction in the mouse heart (6, 41). Since MYH7b mRNA levels appear much lower than those of other muscle myosins, the role of MYH7b protein in vertebrate muscle remains unclear.Here, we show that MYH7b expression is controlled transcriptionally by different stimuli, as well as posttranscriptionally, through a unique alternative splicing event. Moreover, we show that miR-499 acts in a regulatory feedback circuit to control MYH7b activity. Our data reveal the complexity of MYH7b gene regulation and unveil a novel mechanism that uncouples host gene-microRNA coexpression. MATERIALS AND METHODSAnimal use and care. C57/BL6 mice used in the experiments were allowed access to standard soy-based rodent chow and water ad libitum. Unless otherwise noted, C57/BL6 male mice 12 weeks of age were used in the experiments. For altered thyroid hormone conditions, mice were fed an iodine-deficient chow supplemented with 0.15% propylthiouracil ([PTU] Harlan Teklad diet composition TD.95125) ad libitum for 30 days. Mice treated with PTU and triiodothyronine (T 3 ) were injected intraperitoneally with 0.2 g/g T 3 on days 29 and 30 of PTU diet ingestion. Four mice from each thyroid condition were sacrificed at 12 weeks of age, and tissues were rapidly excised and froze...

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Section: Discussionmentioning

confidence: 99%

Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping

Bell

Buvoli

Leinwand

2010

Molecular and Cellular Biology

122

138

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“…The SP family of transcription factors, including Sp3, is highly regulated at the posttranslational level. Although Sp3 is able to up- ( 35,36 ) and down-regulate gene transcription (37)(38)(39), phosphorylation is generally associated with increased DNA binding activity and, consequently, increased transcriptional activation ( 35,40 ). Modifi cations such as acetylation have also been described to activate ( 21 ) and repress ( 41 ) Sp3 transcriptional activity, whereas sumoylated Sp3 signifi cantly represses transcription (42)(43)(44).…”

Section: Downloaded Frommentioning

confidence: 99%

Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway

Nunes

Moutinho

Milagre

et al. 2012

Journal of Lipid Research

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“…Fetal sarcomeric and fetal metabolic gene programs are activated by ␣-agonists and seem to require Sp elements combined with increased binding of their respective factors Sp1 and Sp3. Sp factors have also been implicated in skeletal muscle hypertrophy and inactivity (30). In adult skeletal muscle, ␤-myosin heavy chain (␤-MHC) gene expression is primarily restricted to slow-twitch type I fibers; however, its expression is downregulated in response to muscle inactivity.…”

Section: Sp3 Represses ϫ268ctnt Promoter Activitymentioning

confidence: 99%

“…In adult skeletal muscle, ␤-myosin heavy chain (␤-MHC) gene expression is primarily restricted to slow-twitch type I fibers; however, its expression is downregulated in response to muscle inactivity. Tsika et al (30) showed that, under non-weight-bearing conditions, downregulation of ␤-MHC gene expression is associated with increased binding of Sp3 to GC-rich elements. Conversely, binding of Sp3 to these elements decreased, whereas Sp1 binding increased, with nuclear extracts from plantaris muscle exposed to mechanical overload, a stimulus that increases ␤-MHC gene expression.…”

Section: Sp3 Represses ϫ268ctnt Promoter Activitymentioning

confidence: 99%

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

Azakie¹,

Fineman²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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Azakie, Anthony, Jeffrey R. Fineman, and Youping He. Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol 291: H600 -H611, 2006. First published April 14, 2006; doi:10.1152/ajpheart.01305.2005.-Combinatorial interactions between cis elements and trans-acting factors are required for regulation of cardiac gene expression during normal cardiac development and pathological cardiac hypertrophy. Sp factors bind GC boxes and are implicated in recruitment and assembly of the basal transcriptional complex. In this study, we show that the cardiac troponin T (cTnT) promoter contains a GC box that is necessary for basal and cAMP-mediated activity of cTnT promoter constructs transfected in embryonic cardiomyocytes. Cardiac nuclear proteins bind the cTnT GC box in a sequence-specific fashion and consist of Sp1, Sp2, and Sp3 protein factors. By chromatin immunoprecipitation, Sp1 binds the cTnT promoter "in vivo." Cotransfected Sp1 trans-activates the cTnT promoter in cardiomyocytes in culture. Sp3 represses Sp1-mediated transcriptional activation of the cTnT gene in embryonic cardiomyocytes. Sp3 repression of Sp1-mediated cTnT promoter activation is dose dependent, inferring a mechanism of competitive binding/inhibition. To evaluate the role of Sp factors in cardiac gene expression in vivo, we have established a clinically relevant animal model of pathological cardiac hypertrophy where the fetal cardiac program is activated. In this animal model, cardiac hypertrophy results from increased left-right shunting, volume loading of the left ventricle, and pressure loading of the right ventricle. Sp1 expression is increased in all four hypertrophied cardiac chambers, whereas Sp3 expression is diminished. This observation is consistent with the in vitro activating function of Sp1 and inhibitory effects of Sp3 on activity of cTnT promoter constructs. Sp factor levels are modulated during the hypertrophic cardiac program in vivo. promoter function; transcription factors; cardiac differentiation; cell specification; cardiac muscle hypertrophy THE SP FAMILY OF TRANSCRIPTION factors is characterized by a series of three zinc fingers at the carboxy-terminal end of the protein that are preceded by glutamine-and serine-threoninerich domains (8, 28). Sp proteins bind GC boxes and the related GT/CACC-box motifs and are implicated in the recruitment and assembly of the basal transcriptional complex. GC boxes have been implicated in the regulation of cardiac promoters, but the direct effects of Sp family members on cardiac promoter activity have not been defined.We use the cardiac troponin T (cTnT) gene promoter as a model of cardiac-specific gene expression during myocardial differentiation (3,5,22,27,29). The cTnT promoter is developmentally regulated by numerous promoter motifs and transacting factors, including MCAT or transcription enhancer factor-1 (TEF-1) binding sites, AT-rich/monocyte enhancer factor-2 (MEF-2) bindin...

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Sp3 Proteins Negatively Regulate β Myosin Heavy Chain Gene Expression during Skeletal Muscle Inactivity

Cited by 23 publications

References 53 publications

Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping

Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping

Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

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