MEF-2 and Oct-1 Bind to Two Homologous Promoter Sequence Elements and Participate in the Expression of a Skeletal Muscle-specific Gene

Lakich, M. M.; Diagana, Thierry T.; North, Daniel L.; Whalen, Robert G.

doi:10.1074/jbc.273.24.15217

Cited by 49 publications

(49 citation statements)

References 59 publications

(46 reference statements)

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“…Within this region, A/T1 and an adjacent bicoid consensus site (GTTAATCCG) bind nuclear proteins from Sol8 myotubes (see above and reference 9). Although the identity of the factor(s) binding to these sequences is not established, recently a similar AT-rich element in the murine IIB myosin heavy chain gene promoter, named mAT2 site, has been shown to bind Oct-1, a protein that contains a POU binding domain (36). Similarly, sequences related to the GTT AATCCG site, mutation of which results in the loss of SURE activity in the stably transfected Sol8 myotubes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Fiber-Type-Specific Transcription of the Troponin I Slow Gene Is Regulated by Multiple Elements

Calvo

Venepally

Cheng

et al. 1999

Molecular and Cellular Biology

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The regulatory elements that restrict transcription of genes encoding contractile proteins specifically to either slow-or fast-twitch skeletal muscles are unknown. As an initial step towards understanding the mechanisms that generate muscle diversity during development, we have identified a 128-bp troponin I slow upstream element (SURE) and a 144-bp troponin I fast intronic element (FIRE) that confer fiber type specificity in transgenic mice (M. Nakayama et al., Mol. Cell. Biol. 16:2408-2417, 1996). SURE and FIRE have maintained the spatial organization of four conserved motifs (3 to 5): an E box, an AT-rich site (A/T2) that binds MEF-2, a CACC site, and a novel CAGG motif. Troponin I slow (TnIs) constructs harboring mutations in these motifs were analyzed in transiently and stably transfected Sol8 myocytes and in transgenic mice to assess their function. Mutations of the E-box, A/T2, and CAGG motifs completely abolish transcription from the TnI SURE. In contrast, mutation of the CACC motif had no significant effect in transfected myocytes or on the slow-specific transcription of the TnI SURE in transgenic mice. To assess the role of E boxes in fiber type specificity, a chimeric enhancer was constructed in which the E box of SURE was replaced with the E box from FIRE. This TnI E box chimera, which lacks the SURE NFAT site, confers essentially the same levels of transcription in transgenic mice as those conferred by wild-type SURE and is specifically expressed in slow-twitch muscles, indicating that the E box on its own cannot determine the fiber-type-specific expression of the TnI promoter. The importance of the 5 half of SURE, which bears little homology to the TnI FIRE, in muscle-specific expression was analyzed by deletion and linker scanning analyses. Removal of the 5 half of SURE (؊846 to ؊811) results in the loss of expression in stably transfected but not in transiently expressing myocytes. Linker scanning mutations identified sequences in this region that are necessary for the function of SURE when integrated into chromatin. One of these sites (GTTAATCCG), which is highly homologous to a bicoid consensus site, binds to nuclear proteins from several mesodermal cells. These results show that multiple elements are involved in the muscle-specific activity of the TnIs promoter and that interactions between upstream and downstream regions of SURE are important for transcription in the context of native chromatin.Skeletal muscle commitment, differentiation, and maturation are largely controlled by the transcriptional regulation of genes encoding channels, receptors, metabolic enzymes, and muscle-specific contractile proteins (8, 52). Whereas our understanding of the transcription factors regulating the commitment and differentiation of myocytes has advanced significantly in the past years, little is known about the factors that regulate fiber type diversity during muscle maturation. During postnatal development, following the innervation of muscles by motoneurons, distinct isoforms of myosin heavy chains and ot...

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Section: Discussionmentioning

confidence: 99%

Fiber-Type-Specific Transcription of the Troponin I Slow Gene Is Regulated by Multiple Elements

Calvo

Venepally

Cheng

et al. 1999

Molecular and Cellular Biology

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“…We focused on two elements in the proximal promoter region, the AT2 and the CArG-like elements, because these had been demonstrated previously to act as activators of the IIb MyHC promoter (12,27). The IIb AT2 element binds both Oct-1 and MEF-2, but binding is greatly reduced for the IIa and IId/x AT2 elements (Fig.…”

Section: Discussionmentioning

confidence: 99%

Myocyte Enhancer Factor-2 and Serum Response Factor Binding Elements Regulate Fast Myosin Heavy Chain Transcription in Vivo

Allen¹,

Weber²,

Sycuro³

et al. 2005

Journal of Biological Chemistry

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Adult fast muscle fibers express distinct myosin heavy chains (MyHC) in differing proportions, but the mechanisms underlying their differential expression remain undefined. We used a variety of in vitro and in vivo approaches to explore the contribution of transcriptional regulation to adult fast MyHC expression. Here we show that 800 -1000 bp of a sequence upstream of the three mouse adult fast MyHC genes (Ia, IIb, and IId/x) are sufficient to drive muscle-specific and fiber-specific expression in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation. Finally, we demonstrate that regions upstream of 300 bp modulate the effects of these elements. Together, these data demonstrate that the quantitative differences in MyHC expression in mouse skeletal muscle have evolved at least in part through the elimination of positive-acting transcription factor binding sites.

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“…8A, lane 4, Iono Ab). The third, lower complex probably represents a palindrome-binding protein (Pal-BP) previously identified by Lakich et al (30). Binding of all three protein complexes is greater in ionophoretreated myotube nuclear extract compared with untreated myotube nuclear extracts (Fig.…”

Section: Responsiveness Of the Myhc Promoters To Intracellularmentioning

confidence: 99%

“…8A). Based on previous research (30), 2 the upper binding activity is actually a doublet likely to represent binding of MEF-2 family members in the uppermost band, whereas the slightly lower band represents Oct-1 binding. The addition of a polyclonal antibody against MEF-2 results in a supershift of the uppermost band in the complex (Fig.…”

Section: Responsiveness Of the Myhc Promoters To Intracellularmentioning

confidence: 99%

Intracellular Calcium and Myosin Isoform Transitions

Allen

Leinwand

2002

Journal of Biological Chemistry

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Intracellular calcium levels can have profound effects on muscle biology via alterations in gene expression. In particular, intracellular calcium levels increase during muscle activation and are thought to underlie fast-toslow shifts in muscle gene expression. In the present work, we determined that increased intracellular calcium has a significant effect on the activity of the adult fast myosin heavy chain (MyHC) promoters in the order of MyHC IIa > > IId/x > IIb. We have identified the pathways by which the calcium signal mediates increased activation of the MyHC IIa promoter. Inhibition of calcineurin or calcium-calmodulin kinase greatly attenuates ionophore-induced activation of the MyHC IIa promoter, whereas protein kinase C inhibitors have no effect. Inhibition and overexpression studies with members of the mitogen-activated protein kinase family reveal roles for MEK1/MEK2 and MEKK1, but not p38 or phosphatidylinositol 3-kinase. Downstream mediators of these effects are the activities of the MEF-2 and NFAT transcription factors, whose binding sites in the MyHC IIa promoter are required for calcium-induced activation of the MyHC IIa promoter.

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MEF-2 and Oct-1 Bind to Two Homologous Promoter Sequence Elements and Participate in the Expression of a Skeletal Muscle-specific Gene

Cited by 49 publications

References 59 publications

Fiber-Type-Specific Transcription of the Troponin I Slow Gene Is Regulated by Multiple Elements

Fiber-Type-Specific Transcription of the Troponin I Slow Gene Is Regulated by Multiple Elements

Myocyte Enhancer Factor-2 and Serum Response Factor Binding Elements Regulate Fast Myosin Heavy Chain Transcription in Vivo

Intracellular Calcium and Myosin Isoform Transitions

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