Target gene selectivity of the myogenic basic helix–loop–helix transcription factor myogenin in embryonic muscle

Davie, Judith K.; Cho, Jang Hyeon; Meadows, Eric; Flynn, Jesse M.; Knapp, Jennifer R.; Klein, William H.

doi:10.1016/j.ydbio.2007.08.014

Cited by 55 publications

(50 citation statements)

References 41 publications

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“…Equally surprising is the partial repression of MyoD. While it is not unexpected that myogenin would contribute to the expression of MyoD, the expression of MyoD in Myog-null animals is not significantly altered (7,19,58). How CIITA represses Myog and MyoD is not currently understood, but we hypothesize that the recruitment of CIITA through the interaction with myogenin causes a repression at promoters that other transcriptional activators cannot overcome.…”

Section: Discussionmentioning

confidence: 83%

Gamma Interferon Modulates Myogenesis through the Major Histocompatibility Complex Class II Transactivator, CIITA

Londhe

Davie

2011

Molecular and Cellular Biology

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Gamma interferon (IFN-␥) is an inflammatory cytokine that has complex effects on myogenesis. Here, we show that the IFN-␥-induced inhibition of myogenesis is mediated by the major histocompatibility complex (MHC) class II transactivator, CIITA, which binds to myogenin and inhibits its activity. In IFN-␥-treated myoblasts, the inhibition of muscle-specific genes includes the expression of myogenin itself, while in myotubes, myogenin expression is unaffected. Thus, CIITA appears to act by both repressing the expression and inhibiting the activity of myogenin at different stages of myogenesis. Stimulation by IFN-␥ in skeletal muscle cells induces CIITA expression as well as MHC class II gene expression. The IFN-␥-mediated repression is reversible, with myogenesis proceeding normally upon removal of IFN-␥. Through overexpression studies, we confirm that the expression of CIITA, independent of IFN-␥, is sufficient to inhibit myogenesis. Through knockdown studies, we also demonstrate that CIITA is necessary for the IFN-␥-mediated inhibition of myogenesis. Finally, we show that CIITA, which lacks DNA binding activity, is recruited to muscle-specific promoters coincident with reductions in RNA polymerase II recruitment. Thus, this work reveals how IFN-␥ modulates myogenesis and demonstrates a key role for CIITA in this process.Gamma interferon (IFN-␥) is an inflammatory cytokine that was first identified as an antiviral factor. IFN-␥ is a pleiotropic cytokine that regulates different immune responses and influences many physiological processes. Many studies have also shown that IFN-␥ influences skeletal muscle homeostasis and repair. Transient administration of exogenous IFN-␥ has been shown to improve healing of skeletal muscle and limit fibrosis (14). Endogenous IFN-␥ is required for efficient muscle regeneration, as mice lacking IFN-␥ show impaired muscle regeneration following cardiotoxin-induced damage (6). Expression of IFN-␥ is robust in proliferating C2C12 cells, but expression is diminished in differentiated C2C12 cells (6). Exogenous IFN-␥ influences the proliferation and differentiation of cultured myoblasts and appears to have a direct role on gene expression (25,26,28,48).Myoblasts have been shown to express immunological properties such as the complement component of both the classical and alternative pathways and major histocompatibility complex (MHC) genes. Exogenous IFN-␥ treatment has been shown to increase the expression of MHC class II genes, complement C components, intracellular adhesion molecule (Icam1), chemokine (C-C motif) ligand 5 (Ccl5; RANTES), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10; Ip10) (15,25,28,48). It is not currently known how IFN-␥ mediates these transcriptional effects in myoblasts.The positive role for IFN-␥ established in muscle healing and repair suggests that this cytokine plays an important role in muscle biology. However, IFN-␥ signaling is likely to be tightly regulated, as negative effects of IFN-␥ have been observed as well. Whe...

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Section: Discussionmentioning

confidence: 83%

Gamma Interferon Modulates Myogenesis through the Major Histocompatibility Complex Class II Transactivator, CIITA

Londhe

Davie

2011

Molecular and Cellular Biology

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“…Moreover, we have previously shown that the hormone induces myosin heavy chain (MHC) and myogenin in the early stage of differentiation of C2C12 cells grown in low-serum medium (Buitrago et al 2012). The presence of myogenin ensures MHC expression and modulates the subsequent myotube development, demonstrating that myogenin acts early in the determination of myoblast differentiation (Davie et al 2007). In this work, 1,25D induced an acute and steady increase in myogenin expression in C2C12 WT cells, while myogenin protein levels remained undetectable in C2C12-VDR cells and when p38 was inhibited.…”

Section: Discussionmentioning

confidence: 99%

“…Both P21 waf1/Cip1 and p27 Kip1 are CKIs; however, they have specific actions in myogenic differentiation (el-Deiry et al 1994, Guo et al 1994. The induction of p27 Kip1 CKI is an early critical step of the N-cadherin-dependent signaling involved in myogenesis, showing an active role of p27 Kip1 CKI in the decision of myoblasts to undergo differentiation (Messina et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells

Irazoqui¹,

Boland²,

Buitrago³

2014

Journal of Molecular Endocrinology

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Previously, we have reported that 1,25(OH) 2 -vitamin D 3 (1,25D) activates p38 MAPK (p38) in a vitamin D receptor (VDR)-dependent manner in proliferative C2C12 myoblast cells. It was also demonstrated that 1,25D promotes muscle cell proliferation and differentiation. However, we did not study these hormone actions in depth. In this study we have investigated whether the VDR and p38 participate in the signaling mechanism triggered by 1,25D. In C2C12 cells, the VDR was knocked down by a shRNA, and p38 was specifically inhibited using SB-203580. Results from cell cycle studies indicated that hormone stimulation prompts a peak of S-phase followed by an arrest in the G0/G1-phase, events which were dependent on VDR and p38. Moreover, 1,25D increases the expression of cyclin D3 and the cyclin-dependent kinase inhibitors, p21Waf1/Cip1 and p27 Kip1 , while cyclin D1 protein levels did not change during G0/G1 arrest. In all these events, p38 and VDR were required. At the same time, a 1,25D-dependent acute increase in myogenin expression was observed, indicating that the G0/G1 arrest of cells is a pro-differentiative event. Immunocytochemical assays revealed co-localization of VDR and cyclin D3, promoted by 1,25D in a p38-dependent manner. When cyclin D3 expression was silenced, VDR and myogenin levels were downregulated, indicating that cyclin D3 was required for 1,25D-induced VDR expression and the concomitant entrance into the differentiation process. In conclusion, the VDR and p38 are involved in control of the cellular cycle by 1,25D in skeletal muscle cells, providing key information on the mechanisms underlying hormone regulation of myogenesis.

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“…Myogenin regulates various genes necessary for skeletal muscle differentiation, including the expression of myosin heavy chain, troponin and another muscle-specific transcription factor, MRF4 (Perry and Rudnick, 2000;Davie et al, 2007). Interestingly, while osteogenic markers started to appear at a Pi concentration of 3~5 mM, the inhibition of myogenesis manifested in a decrease of the fusion index, and myogenin expression was not observed until the Pi concentration reached 7 mM.…”

Section: Pi-induced Osteogenesis and Inhibited Myogenesis In Skeletalmentioning

confidence: 99%

Ectopic Calcification is Caused by Elevated Levels of Serum Inorganic Phosphate in Mdx Mice

Kikkawa

Ohno

Nagata

et al. 2009

Cell Struct. Funct.

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ABSTRACT. Ectopic calcification occurs in the skeletal muscle of mdx mice, a dystrophin-deficient animal model of Duchenne muscular dystrophy. The purpose of this study was to clarify the mechanism of the calcification. The calcified deposits were identified as hydroxyapatite, a crystallized form of calcium phosphate, and the serum inorganic phosphate (Pi) level in the mdx mice was approximately 1.4 times higher than that in the normal B10 mice, suggesting that Pi plays a critical role in the ectopic calcification. When C2C12 mouse myoblasts were cultured under high-Pi conditions, myogenic differentiation was retarded while the expression of osteogenic markers such as osteocalcin and Runx2 were upregulated. This was followed by the generation of calcium deposition. Moreover, ectopic calcification reduced to an undetectable level in most of the mdx mice fed a Pireduced diet. We therefore conclude that the Pi-induced osteogenesis of muscle cells is responsible for ectopic calcification in the skeletal muscle of mdx mice.

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Target gene selectivity of the myogenic basic helix–loop–helix transcription factor myogenin in embryonic muscle

Cited by 55 publications

References 41 publications

Gamma Interferon Modulates Myogenesis through the Major Histocompatibility Complex Class II Transactivator, CIITA

Gamma Interferon Modulates Myogenesis through the Major Histocompatibility Complex Class II Transactivator, CIITA

Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells

Ectopic Calcification is Caused by Elevated Levels of Serum Inorganic Phosphate in Mdx Mice

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