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

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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IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

International Journal of Molecular Sciences ◽

10.3390/ijms21010182 ◽

2019 ◽

Vol 21 (1) ◽

pp. 182 ◽

Cited By ~ 4

Author(s):

Yukako Tokutake ◽

Keita Yamada ◽

Satoko Hayashi ◽

Wataru Arai ◽

Takafumi Watanabe ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Differentiation ◽

C2c12 Cells ◽

Myoblast Differentiation ◽

Skeletal Muscle Differentiation ◽

Cyclin Dependent Kinase ◽

Early Differentiation ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1–XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1–XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1–XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1–XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.

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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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Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease

Brain ◽

10.1093/brain/awz172 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2380-2401 ◽

Cited By ~ 9

Author(s):

Saurav Brahmachari ◽

Saebom Lee ◽

Sangjune Kim ◽

Changqing Yuan ◽

Senthilkumar S Karuppagounder ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Critical Role ◽

Trna Synthetase ◽

Loss Of Function ◽

Substrate Protein ◽

Finger Protein ◽

Sporadic Parkinson’S Disease

Abstract α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

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

10.1101/2020.02.21.960484 ◽

2020 ◽

Author(s):

Gist H. Farr ◽

Bingsi Li ◽

Maurizio Risolino ◽

Nathan M. Johnson ◽

Zizhen Yao ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Development ◽

Muscle Differentiation ◽

Mouse Embryos ◽

Fast Muscle ◽

Fiber Types ◽

Skeletal Muscle Differentiation ◽

Homeodomain Proteins ◽

Evolutionarily Conserved ◽

Fast Twitch

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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A Cys2/His2 Zinc Finger Protein Acts as a Repressor of the Green Revolution Gene SD1/OsGA20ox2 in Rice (Oryza sativa L.)

Plant and Cell Physiology ◽

10.1093/pcp/pcaa120 ◽

2020 ◽

Author(s):

Min Duan ◽

Xiao-Juan Ke ◽

Hong-Xia Lan ◽

Xi Yuan ◽

Peng Huang ◽

...

Keyword(s):

Plant Growth ◽

Zinc Finger ◽

Growth And Development ◽

Zinc Finger Protein ◽

Green Revolution ◽

Critical Role ◽

Transcriptional Repressor ◽

Fine Tuning ◽

Plant Growth And Development ◽

Finger Protein

Abstract Gibberellins (GAs) play important roles in the regulation of plant growth and development. The green revolution gene SD1 encoding gibberellin 20-oxidase 2 (GA20ox2) has been widely used in modern rice breeding. However, the molecular mechanism of how SD1/OsGA20ox2 expression is regulated remains unclear. Here, we report a Cys2/His2 zinc finger protein ZFP207 acting as a transcriptional repressor of OsGA20ox2. ZFP207 was mainly accumulated in young tissues and more specifically in culm nodes. ZFP207-overexpression (ZFP207OE) plants displayed semidwarfism phenotype and small grains by modulating cell length. RNA interference of ZFP207 caused increased plant height and grain length. The application of exogenous GA3 could rescue the semidwarf phenotype of ZFP207OE rice seedlings. Moreover, ZFP207 repressed the expression of OsGA20ox2 via binding to its promoter region. Taken together, ZFP207 acts as a transcriptional repressor of SD1/OsGA20ox2 and it may play a critical role in plant growth and development in rice through the fine-tuning of GA biosynthesis .

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Abstract 5045: Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.

10.1158/1538-7445.am2013-5045 ◽

2013 ◽

Author(s):

Raffaella Spina ◽

Gessica Filocamo ◽

Enrico Iaccino ◽

Stefania Scicchitano ◽

Michela Lupia ◽

...

Keyword(s):

Zinc Finger ◽

Zinc Finger Protein ◽

Critical Role ◽

Finger Protein ◽

Tumorigenic Potential

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Aurora kinase A mediated phosphorylation of mPOU is critical for skeletal muscle differentiation

10.1101/589754 ◽

2019 ◽

Author(s):

Dhanasekaran Karthigeyan ◽

Arnab Bose ◽

Ramachandran Boopathi ◽

Vinay Jaya Rao ◽

Hiroki Shima ◽

...

Keyword(s):

Skeletal Muscle ◽

Aurora Kinase ◽

Muscle Differentiation ◽

Negative Regulator ◽

Myoblast Differentiation ◽

C2c12 Myoblast ◽

Skeletal Muscle Differentiation ◽

Skeletal Myogenesis ◽

Aurora Kinase A ◽

Kinase A

AbstractAurora kinases are Ser/Thr-directed protein kinases which play pivotal roles in mitosis. Recent evidences highlight the importance of these kinases in non-mitotic biological events like skeletal myogenesis. Our earlier study identified POU6F1 (or mPOU) as a novel Aurora kinase A (AurkA) substrate. Here, we report that AurkA phosphorylates POU6F1 at Ser197 and inhibits its DNA binding ability. Delving into POU6F1 physiology, we find that the phospho-mimic (S197D) POU6F1 mutant exhibits enhancement, while wild type (WT) or phospho-deficient (S197A) mutant shows retardation in C2C12 myoblast differentiation. Interestingly, POU6F1 depletion phenocopies S197D-POU6F1 overexpression in the differentiation context. Collectively, our results signify mPOU as a negative regulator of skeletal muscle differentiation and strengthens the importance of AurkA in skeletal myogenesis.

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MicroRNA-24-3p promotes skeletal muscle differentiation and regeneration by regulating HMGA1

10.21203/rs.3.rs-976465/v1 ◽

2021 ◽

Author(s):

Paromita Dey ◽

Miles A Soyer ◽

Bijan K Dey

Keyword(s):

Skeletal Muscle ◽

Tibialis Anterior Muscle ◽

High Mobility ◽

Muscle Differentiation ◽

Skeletal Muscle Regeneration ◽

Myoblast Differentiation ◽

Skeletal Muscle Differentiation ◽

Muscle Stem Cells ◽

Downstream Target

Abstract Numerous studies have established the critical roles of microRNAs in regulating posttranscriptional gene expression in diverse biological processes. Here, we report on the role and mechanism of miR-24-3p in skeletal muscle differentiation and regeneration. miR-24-3p promotes myoblast differentiation and skeletal muscle regeneration by directly targeting high mobility group AT-hook 1 (HMGA1) and regulating it and its direct downstream target, the inhibitor of differentiation 3 (ID3). miR-24-3p knockdown in neonatal mice increases PAX7-positive proliferating muscle stem cells (MuSCs) by derepressing Hmga1 and Id3 . Similarly, inhibiting miR24-3p in the tibialis anterior muscle prevents Hmga1 and Id3 downregulation and impairs regeneration. These findings provide evidence that the miR-24-3p/HMGA1/ID3 axis is required for MuSC differentiation and regeneration in vivo .

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A novel, tissue-restricted zinc finger protein (HF-1b) binds to the cardiac regulatory element (HF-1b/MEF-2) in the rat myosin light-chain 2 gene

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.4432-4444.1993 ◽

1993 ◽

Vol 13 (7) ◽

pp. 4432-4444

Author(s):

H Zhu ◽

V T Nguyen ◽

A B Brown ◽

A Pourhosseini ◽

A V Garcia ◽

...

Keyword(s):

Skeletal Muscle ◽

Zinc Finger ◽

Cardiac Tissue ◽

Zinc Finger Protein ◽

Regulatory Element ◽

Binding Activity ◽

Cardiac Muscle Cells ◽

Specific Expression ◽

Isolation And Characterization ◽

Finger Protein

The AT-rich element MEF-2 plays an important role in the maintenance of the muscle-specific expression of a number of cardiac and skeletal muscle genes. In the MLC-2 gene, an AT-rich element (HF-1b) which contains a consensus MEF-2 site is required for cardiac tissue-specific expression. The present study reports the isolation and characterization of a cDNA which encodes a novel C2H2 zinc finger (HF-1b) that binds in a sequence-specific manner to the HF-1b/MEF-2 site in the MLC-2 promoter. A number of independent criteria suggest that this HF-1b zinc finger protein is a component of the endogenous HF-1b/MEF-2 binding activity in cardiac muscle cells and that it can serve as a transcriptional activator of the MLC-2 promoter in transient assays. These studies suggest that, in addition to the previously reported RSRF proteins, structurally divergent transcriptional factors can bind to MEF-2-like sites in muscle promoters. These results underscore the complexity of the regulation of the muscle gene program via these AT-rich elements in cardiac and skeletal muscle.

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6-Bromoindirubin-3′-oxime intercepts GSK3 signaling to promote and enhance skeletal muscle differentiation affecting miR-206 expression in mice

Scientific Reports ◽

10.1038/s41598-019-54574-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Elvira Ragozzino ◽

Mariarita Brancaccio ◽

Antonella Di Costanzo ◽

Francesco Scalabrì ◽

Gennaro Andolfi ◽

...

Keyword(s):

Skeletal Muscle ◽

Myogenic Differentiation ◽

Muscle Differentiation ◽

C2c12 Cells ◽

Skeletal Muscle Differentiation ◽

Myoblast Proliferation ◽

Enhanced Expression ◽

Pharmacologically Active

AbstractDystrophies are characterized by progressive skeletal muscle degeneration and weakness as consequence of their molecular abnormalities. Thus, new drugs for restoring skeletal muscle deterioration are critically needed. To identify new and alternative compounds with a functional role in skeletal muscle myogenesis, we screened a library of pharmacologically active compounds and selected the small molecule 6-bromoindirubin-3′-oxime (BIO) as an inhibitor of myoblast proliferation. Using C2C12 cells, we examined BIO’s effect during myoblast proliferation and differentiation showing that BIO treatment promotes transition from cell proliferation to myogenic differentiation through the arrest of cell cycle. Here, we show that BIO is able to promote myogenic differentiation in damaged myotubes in-vitro by enriching the population of newly formed skeletal muscle myotubes. Moreover, in-vivo experiments in CTX-damaged TA muscle confirmed the pro-differentiation capability of BIO as shown by the increasing of the percentage of myofibers with centralized nuclei as well as by the increasing of myofibers number. Additionally, we have identified a strong correlation of miR-206 with BIO treatment both in-vitro and in-vivo: the enhanced expression of miR-206 was observed in-vitro in BIO-treated proliferating myoblasts, miR-206 restored expression was observed in a forced miR-206 silencing conditions antagomiR-mediated upon BIO treatment, and in-vivo in CTX-injured muscles miR-206 enhanced expression was observed upon BIO treatment. Taken together, our results highlight the capacity of BIO to act as a positive modulator of skeletal muscle differentiation in-vitro and in-vivo opening up a new perspective for novel therapeutic targets to correct skeletal muscle defects.

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