Evolutionarily conserved regulation of embryonic fast-twitch skeletal muscle differentiation by Pbx factors

SummaryVertebrate skeletal muscles are composed of both slow-twitch and fast-twitch fiber types. How the differentiation of distinct fiber types is activated during embryogenesis is not well characterized. Skeletal muscle differentiation is initiated by the activity of the myogenic basic helix-loop-helix (bHLH) transcription factors Myf5, Myod1, Myf6, and Myog. Myod1 functions as a muscle master regulatory factor and directly activates muscle differentiation genes, including those specific to both slow and fast muscle fibers. Our previous studies showed that Pbx TALE-class homeodomain proteins bind with Myod1 on the promoter of the zebrafish fast muscle gene mylpfa and are required for proper activation of mylpfa expression and the fast-twitch muscle-specific differentiation program in zebrafish embryos. Pbx proteins have also been shown to bind regulatory regions of muscle differentiation genes in mammalian muscle cells in culture. Here, we use new zebrafish mutant strains to confirm the essential roles of zebrafish Pbx factors in embryonic fast muscle differentiation. Furthermore, we examine the requirements for Pbx genes in mouse embryonic skeletal muscle differentiation, an area that has not been investigated in the mammalian embryo. Removing Pbx1 function from skeletal muscle in Myf5Cre/+;Pbx1fl/fl mouse embryos has minor effects on embryonic muscle development. However, concomitantly deleting Pbx2 function in Myf5Cre/+;Pbx1fl/fl;Pbx2-/- mouse embryos causes delayed activation and reduced expression of fast muscle differentiation genes. In the mouse, Pbx1/Pbx2-dependent fast muscle genes closely match those that have been previously shown to be dependent on murine Six1 and Six4. This work establishes evolutionarily conserved requirements for Pbx factors in embryonic fast muscle differentiation. Our studies are revealing how Pbx homeodomain proteins help direct specific cellular differentiation pathways.

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Zfp422 promotes skeletal muscle differentiation by regulating EphA7 to induce appropriate myoblast apoptosis

Cell Death and Differentiation ◽

10.1038/s41418-019-0448-9 ◽

2019 ◽

Vol 27 (5) ◽

pp. 1644-1659 ◽

Cited By ~ 1

Author(s):

Yaping Nie ◽

Shufang Cai ◽

Renqiang Yuan ◽

Suying Ding ◽

Xumeng Zhang ◽

...

Keyword(s):

Skeletal Muscle ◽

Zinc Finger ◽

Muscle Development ◽

Zinc Finger Protein ◽

Critical Role ◽

Muscle Differentiation ◽

C2c12 Cells ◽

Myoblast Differentiation ◽

Skeletal Muscle Differentiation ◽

Finger Protein

Abstract Zinc finger protein 422 (Zfp422) is a widely expressed zinc finger protein that serves as a transcriptional factor to regulate downstream gene expression, but until now, little is known about its roles in myogenesis. We found here that Zfp422 plays a critical role in skeletal muscle development and regeneration. It highly expresses in mouse skeletal muscle during embryonic development. Specific knockout of Zfp422 in skeletal muscle impaired embryonic muscle formation. Satellite cell-specific Zfp422 deletion severely inhibited muscle regeneration. Myoblast differentiation and myotube formation were suppressed in Zfp422-deleted C2C12 cells, isolated primary myoblasts, and satellite cells. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) revealed that Zfp422 regulated ephrin type-A receptor 7 (EphA7) expression by binding an upstream 169-bp DNA sequence, which was proved to be an enhancer of EphA7. Knocking EphA7 down in C2C12 cells or deleting Zfp422 in myoblasts will inhibit cell apoptosis which is required for myoblast differentiation. These results indicate that Zfp422 is essential for skeletal muscle differentiation and fusion, through regulating EphA7 expression to maintain proper apoptosis.

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The SMYD3 methyltransferase promotes myogenesis by activating the myogenin regulatory network

Scientific Reports ◽

10.1038/s41598-019-53577-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Roberta Codato ◽

Martine Perichon ◽

Arnaud Divol ◽

Ella Fung ◽

Athanassia Sotiropoulos ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Development ◽

Myogenic Differentiation ◽

Muscle Differentiation ◽

Skeletal Muscle Differentiation ◽

Skeletal Muscle Development ◽

Genome Wide ◽

Coordinated Expression

AbstractThe coordinated expression of myogenic regulatory factors, including MyoD and myogenin, orchestrates the steps of skeletal muscle development, from myoblast proliferation and cell-cycle exit, to myoblast fusion and myotubes maturation. Yet, it remains unclear how key transcription factors and epigenetic enzymes cooperate to guide myogenic differentiation. Proteins of the SMYD (SET and MYND domain-containing) methyltransferase family participate in cardiac and skeletal myogenesis during development in zebrafish, Drosophila and mice. Here, we show that the mammalian SMYD3 methyltransferase coordinates skeletal muscle differentiation in vitro. Overexpression of SMYD3 in myoblasts promoted muscle differentiation and myoblasts fusion. Conversely, silencing of endogenous SMYD3 or its pharmacological inhibition impaired muscle differentiation. Genome-wide transcriptomic analysis of murine myoblasts, with silenced or overexpressed SMYD3, revealed that SMYD3 impacts skeletal muscle differentiation by targeting the key muscle regulatory factor myogenin. The role of SMYD3 in the regulation of skeletal muscle differentiation and myotube formation, partially via the myogenin transcriptional network, highlights the importance of methyltransferases in mammalian myogenesis.

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The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly

The Journal of Cell Biology ◽

10.1083/jcb.201010090 ◽

2011 ◽

Vol 194 (4) ◽

pp. 551-565 ◽

Cited By ~ 66

Author(s):

Yazhong Tao ◽

Ronald L. Neppl ◽

Zhan-Peng Huang ◽

Jianfu Chen ◽

Ru-Hang Tang ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Development ◽

Myogenic Differentiation ◽

Muscle Differentiation ◽

Histone Methyltransferase ◽

Contractile Proteins ◽

Dominant Negative ◽

Myoblast Differentiation ◽

Skeletal Muscle Differentiation ◽

Muscle Gene Expression

The molecular events that modulate chromatin structure during skeletal muscle differentiation are still poorly understood. We report in this paper that expression of the H3-K4 histone methyltransferase Set7 is increased when myoblasts differentiate into myotubes and is required for skeletal muscle development, expression of muscle contractile proteins, and myofibril assembly. Knockdown of Set7 or expression of a dominant-negative Set7 mutant impairs skeletal muscle differentiation, accompanied by a decrease in levels of histone monomethylation (H3-K4me1). Set7 directly interacts with MyoD to enhance expression of muscle differentiation genes. Expression of myocyte enhancer factor 2 and genes encoding contractile proteins is decreased in Set7 knockdown myocytes. Furthermore, we demonstrate that Set7 also activates muscle gene expression by precluding Suv39h1-mediated H3-K9 methylation on the promoters of myogenic differentiation genes. Together, our experiments define a biological function for Set7 in muscle differentiation and provide a molecular mechanism by which Set7 modulates myogenic transcription factors during muscle differentiation.

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Maternal Methyl-Donor Micronutrient Supplementation During Pregnancy Promotes Skeletal Muscle Differentiation and Maturity in Newborn and Weaning Pigs

Frontiers in Nutrition ◽

10.3389/fnut.2020.609022 ◽

2020 ◽

Vol 7 ◽

Author(s):

Qin He ◽

Tiande Zou ◽

Jun Chen ◽

Li Jian ◽

Jia He ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Development ◽

Body Weight Gain ◽

Umbilical Vein ◽

Serum Insulin ◽

Control Diet ◽

Muscle Differentiation ◽

The Body ◽

Skeletal Muscle Differentiation ◽

Methyl Donor

Adequate maternal methyl-donor micronutrient (MET) intake is an important determinant of the organ development and metabolic renovation of offspring. The mechanism involved in skeletal myogenesis and the effect of MET supplementation during pregnancy on the maternal body remain unclear. Thus, this study aimed to investigate the potential effect of methyl donor micronutrients (MET) on skeletal muscle development and metabolism in offspring using pig models. Forty-three Duroc × Erhualian gilts were assigned to two dietary groups during gestation: control diet (CON) and CON diet supplemented with MET (folic acid, methionine, choline, vitamin B6, and vitamin B12). The results showed that maternal MET exposure during pregnancy significantly increased the concentrations of protein, triiodothyronine (T3), and thyroxine (T4) in colostrum and methyl metabolites, including S-adenosylmethionine (SAM), S-adenosyl-L-homocysteine (SAH), 5-methyl-tetrahydrofolate (5-MTHF), and betaine, in the maternal and offspring umbilical vein serum. A similar pattern was demonstrated in the body weight gain and myofiber diameters in offspring. In addition, maternal MET supplementation significantly increased the concentration of offspring serum insulin-like growth factor 1 (IGF-1), T3, and T4; upregulated the mRNA expression of IGF-1 and IGF-1 receptor (IGF-1r) and the phosphorylation level of protein kinases in offspring longissimus dorsi muscle; and upregulated the expression of myogenic genes and fast myosin heavy chain (fast MyHC) in offspring skeletal muscle. Supplementing sows with higher levels of MET during gestation may promote skeletal muscle differentiation and maturity and improve the skeletal muscle mass of the piglets.

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The SMYD3 methyltransferase promotes myogenesis by activating the myogenin regulatory network

10.1101/804633 ◽

2019 ◽

Author(s):

Roberta Codato ◽

Martine Perichon ◽

Arnaud Divol ◽

Ella Fung ◽

Athanassia Sotiropoulos ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Development ◽

Myogenic Differentiation ◽

Muscle Differentiation ◽

Skeletal Muscle Differentiation ◽

Skeletal Muscle Development ◽

Genome Wide ◽

Coordinated Expression

ABSTRACTThe coordinated expression of myogenic regulatory factors, including MyoD and myogenin, orchestrates the steps of skeletal muscle development, from myoblast proliferation and cell-cycle exit, to myoblast fusion and myotubes maturation. Yet, it remains unclear how key transcription factors and epigenetic enzymes cooperate to guide myogenic differentiation. Proteins of the SMYD (SET and MYND domain-containing) methyltransferase family participate in cardiac and skeletal myogenesis during development in zebrafish, Drosophila and mice. Here, we show that the mammalian SMYD3 methyltransferase coordinates skeletal muscle differentiation in vitro. Overexpression of SMYD3 in myoblasts promoted muscle differentiation and myoblasts fusion. Conversely, silencing of endogenous SMYD3 or its pharmacological inhibition impaired muscle differentiation. Genome-wide transcriptomic analysis of murine myoblasts, with silenced or overexpressed SMYD3, revealed that SMYD3 impacts skeletal muscle differentiation by targeting the key muscle regulatory factor myogenin. The role of SMYD3 in the regulation of skeletal muscle differentiation and myotube formation, partially via the myogenin transcriptional network, highlights the importance of methyltransferases in mammalian myogenesis.

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