Fhl1 as a downstream target of Wnt signaling to promote myogenesis of C2C12 cells

Lee, Jing-Yu; Chien, I-Chun; Lin, Win-Yu; Wu, Shao‐Min; Wei, Bo-Huei; Lee, Yu-En; Lee, Hu-Hui

doi:10.1007/s11010-012-1266-2

Cited by 16 publications

(33 citation statements)

References 53 publications

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“…FHL-1 contains a TCF/LEF binding site, which can be stimulated by b-catenin or Wnt pathway agonist lithium chloride inducing muscle hypertrophy and repressing chondrogenesis. [59,60]. In support of our results, a recent study [61] identified that overexpression of FHL1 in murine MC3T3-E1 cells promotes osteogenesis.…”

Section: Discussionsupporting

confidence: 89%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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Histone three lysine 27 (H3K27) methyltransferase enhancer of zeste homolog 2 (EZH2) is a critical epigenetic modifier, which regulates gene transcription through the trimethylation of the H3K27 residue leading to chromatin compaction and gene repression. EZH2 has previously been identified to regulate human bone marrow-derived mesenchymal stem cells (MSC) lineage specification. MSC lineage specification is regulated by the presence of EZH2 and its H3K27me3 modification or the removal of the H3K27 modification by lysine demethylases 6A and 6B (KDM6A and KDM6B). This study used a bioinformatics approach to identify novel genes regulated by EZH2 during MSC osteogenic differentiation. In this study, we identified the EZH2 targets, ZBTB16, MX1, and FHL1, which were expressed at low levels in MSC. EZH2 and H3K27me3 were found to be present along the transcription start site of their respective promoters. During osteogenesis, these genes become actively expressed coinciding with the disappearance of EZH2 and H3K27me3 on the transcription start site of these genes and the enrichment of the active H3K4me3 modification. Overexpression of EZH2 downregulated the transcript levels of ZBTB16, MX1, and FHL1 during osteogenesis. Small interfering RNA targeting of MX1 and FHL1 was associated with a downregulation of the key osteogenic transcription factor, RUNX2, and its downstream targets osteopontin and osteocalcin. These findings highlight that EZH2 not only acts through the direct regulation of signaling modules and lineage-specific transcription factors but also targets many novel genes important for mediating MSC osteogenic differentiation.

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Section: Discussionsupporting

confidence: 89%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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“…Myoblasts isolated from two EDMD patients harbouring the X281E and K157VfsX46 mutations investigated here exhibit reduced expression of mutant FHL1 and delayed myoblast differentiation (Gueneau et al, 2009). Similarly, shRNA-mediated knock-down of FHL1 impairs myotube formation in vitro (Lee et al, 2012). FHL1 expression is decreased in animal models of disuse atrophy (Loughna et al, 2000), and FHL1 protein expression might be reduced in SPM, XMPMA and RSS, which might further exacerbate the loss of normal FHL1 function caused by mutation.…”

Section: Discussionmentioning

confidence: 81%

“…The four and a half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle (Lee et al, 1998;Brown et al, 1999;Greene et al, 1999;Morgan and Madgwick, 1999), influencing cellular architecture (McGrath et al, 2003;McGrath et al, 2006), myoblast differentiation (Lee et al, 2012), mechanotransduction (Sheikh et al, 2008) and skeletal-muscle fibre size . FHL1 mediates protein-protein interactions through its LIM domains; cysteine-rich double zinc fingers containing the consensus sequence [CX2CX16-23HX2C] X2 [CX2CX16-21CX2(C/H/D)] that facilitate binding to proteins but not DNA (Schmeichel and Beckerle, 1997).…”

Section: Introductionmentioning

confidence: 99%

FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation

Wilding

Mcgrath

Bonne

et al. 2014

Journal of Cell Science

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FHL1 mutations cause several clinically heterogeneous myopathies, including reducing body myopathy (RBM), scapuloperoneal myopathy (SPM) and X-linked myopathy with postural muscle atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates, designated 'reducing bodies', that contain mutant FHL1 are detected in RBM muscle but not in several other FHL1 myopathies. Here, RBM, SPM and XMPMA FHL1 mutants were expressed in C2C12 cells and showed equivalent protein expression to wild-type FHL1. These mutants formed aggregates that were positive for the reducing body stain Menadione-NBT, analogous to RBM muscle aggregates. However, hypertrophic cardiomyopathy (HCM) and Emery-Dreifuss muscular dystrophy (EDMD) FHL1 mutants generally exhibited reduced expression. Wild-type FHL1 promotes myoblast differentiation; however, RBM, SPM and XMPMA mutations impaired differentiation, consistent with a loss of normal FHL1 function. Furthermore, SPM and XMPMA FHL1 mutants retarded myotube formation relative to vector control, consistent with a dominant-negative or toxic function. Mutant FHL1 myotube formation was partially rescued by expression of a constitutively active FHL1-binding partner, NFATc1. This is the first study to show that FHL1 mutations identified in several clinically distinct myopathies lead to similar protein aggregation and impair myotube formation, suggesting a common pathogenic mechanism despite heterogeneous clinical features.

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“…It is important to point out that the mesenchymal markers of airway reactivity chosen by us are markers of myofibroblast differentiation (a-SMA and calponin), a hallmark of chronic lung diseases, such as asthma, and/or have been shown to have increased matrix deposition (fibronectin and collagen III) in the subepithelial space of the airways in asthma (18)(19)(20). Furthermore, the other markers used by us, such as b-catenin and LEF-1, are functional intermediates in the Wnt signaling pathway, a key mediator of myogenesis, justifying their inclusion in our analysis (21)(22)(23). However, it must be pointed out that, in our analysis of the myogenic markers of airway reactivity by both Western blotting and immunofluorescence, we did not differentiate between the mesenchymal and vascular compartments.…”

Section: Discussionmentioning

confidence: 89%

Sex-Specific Perinatal Nicotine-Induced Asthma in Rat Offspring

Liu

Naeem

Tian

et al. 2013

Am J Respir Cell Mol Biol

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Recently, we have suggested that down-regulation of homeostatic mesenchymal peroxisome proliferator-activated receptor g signaling after in utero nicotine exposure might contribute to asthma. Here, we have exploited an in vivo rat model of asthma to determine if the effects of perinatal nicotine exposure on offspring pulmonary function and mesenchymal markers of airway contractility in both tracheal and lung parenchymal tissue are sex specific, and whether the protection afforded by the peroxisome proliferator-activated receptor g agonist, rosiglitazone (RGZ), against the perinatal nicotine-induced effect on offspring lung is also sex specific. Pregnant rat dams received placebo, nicotine, or nicotine plus RGZ daily from Embryonic Day 6 until Postnatal Day 21, at which time lung resistance, compliance, tracheal contractility, and the expression of structural and functional mesenchymal markers of pulmonary contractility were determined. Compared with control animals, perinatal nicotine exposure caused a significant increase in airway resistance and a decrease in airway compliance after a methacholine challenge in both male and female offspring, with more pronounced changes in the males. In contrast to this, the effects of perinatal nicotine exposure on acetylcholine-induced tracheal constriction, along with the expression of its mesenchymal markers, were observed exclusively in the male offspring. Concomitant treatment with RGZ normalized the nicotine-induced alterations in pulmonary function in both sexes, as well as the male-specific effects on acetylcholine-induced tracheal constriction, along with the affected mesenchymal markers. These data suggest that perinatal nicotine exposure causes sex-specific perinatal cigarette smoke exposureinduced asthma, providing a powerful phenotypic model for unequivocally determining the underlying nature of the cell molecular mechanism for this disease.Keywords: nicotine; asthma; pregnancy; peroxisome proliferator-activated receptor g; cigarette smokeThere is strong epidemiologic (1-3) and experimental (4-6) evidence that perinatal exposure to maternal smoking results in detrimental long-term effects on lung growth and function, including significant suppression of alveolarization (7,8), and increased predisposition to asthma (9) in the offspring. Because the mechanisms underlying these adverse pulmonary effects remain incompletely understood, there are no effective preventive or therapeutic interventions. Based on both in vitro and in vivo studies from our laboratory, we have suggested that down-regulation of homeostatic lung mesenchymal peroxisome proliferator-activated receptor (PPAR) g signaling might be a key contributor to chronic lung diseases, such as bronchopulmonary dysplasia and asthma (9-11). We have also shown that perinatal treatment with nicotine increases lung resistance (Rrs), and decreases lung compliance in association with increased tracheal constriction (11), an effect that is blocked by the PPARg agonist, rosiglitazone (RGZ) (11). Mechanistically, we ha...

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Fhl1 as a downstream target of Wnt signaling to promote myogenesis of C2C12 cells

Cited by 16 publications

References 53 publications

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation

Sex-Specific Perinatal Nicotine-Induced Asthma in Rat Offspring

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