Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation

Woodhouse, Samuel; Pugazhendhi, Dhamayanthi; Brien, Patrick; Pell, J. M.

doi:10.1242/dev.096859

Cited by 14 publications

(24 citation statements)

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“…11 These findings imply that EZH2 expression and/or stability is deregulated in PAX3-FOXO1 alveolar RMS. Downregulation of EZH2 prevents PAX3-FOXO1 RMS cell proliferation As EZH2 expression sustains the proliferation of skeletal muscle precursors, [9][10][11] we sought to examine the effect of EZH2 depletion on the proliferation potential of the PAX3-FOXO1 alveolar cell line RH30 cultured in a proliferation (growth) medium. Cells were subjected to a double round (24 h) of RNA interference with a previous validated pool of siRNAs against EZH2 to warrant efficient and sustained silencing and analyzed starting from 24 h after the first siRNA transfection.…”

Section: Resultsmentioning

confidence: 99%

“…8 In undifferentiated muscle cells, EZH2-mediated trimethylation of H3K27 contributes to maintaining the chromatin of muscle genes in a conformation repressive for transcription, supporting the self-renewal and proliferation of progenitor cells. [9][10][11][12][13] At the onset of differentiation, downregulation of EZH2 allows a chromatin conformation permissive for transcription of differentiation genes. [11][12][13] These data highlight the importance of EZH2 in controlling the balance between proliferation and differentiation of myogenic progenitors.…”

Section: Introductionmentioning

confidence: 99%

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The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

et al. 2013

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The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.Oncogene ( Keywords: EZH2; FBXO32; histone methyltransferases; PAX3-FOXO1; rhabdomyosarcoma; Polycomb proteins INTRODUCTION Rhabdomyosarcomas (RMS) are heterogeneous highly malignant tumors, which account for 7-8% of all pediatric malignancies and over half of the soft-tissue sarcomas in children. RMS are classically subdivided in two major histotypes: embryonal (around 70-80%) and alveolar (around 20-30%), the latter often metastatic at diagnosis and showing a high risk of recurrence. 1 In 70% of cases, alveolar RMS is characterized by the chromosomal translocation t(2;13) or t(1;13), resulting in

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

et al. 2013

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“…RT-qPCR, mRNA Seq, and Analysis RT-qPCR was performed as described previously [39]. To isolate activated, proliferating satellite cells from regenerating muscle, the right and left gastrocnemius of knockout and control mice (four mice per genotype) were injected with 50 ll of 10 lM cardiotoxin.…”

Section: Discussionmentioning

confidence: 99%

“…The click chemical reaction was performed after immunostaining with primary and secondary antibodies (see below) and before DAPI staining. Fluorescenceactivated cell sorting (FACS) isolation and satellite cell culture was performed as previously described [39].…”

Section: Mice Regeneration Studies and Satellite Cell Isolationmentioning

confidence: 99%

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p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

et al. 2013

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Stem cell function is essential for the maintenance of adult tissue homeostasis. Controlling the balance between selfrenewal and differentiation is crucial to maintain a receptive satellite cell pool capable of responding to growth and regeneration cues. The mitogen-activated protein kinase p38a has been implicated in the regulation of these processes but its influence in adult muscle remains unknown. Using conditional satellite cell p38a knockout mice we have demonstrated that p38a restricts excess proliferation in the postnatal growth phase while promoting timely myoblast differentiation. Differentiation was still able to occur in the p38a-null satellite cells, however, but was delayed. An absence of p38a resulted in a postnatal growth defect along with the persistence of an increased reservoir of satellite cells into adulthood. This population was still capable of responding to cardiotoxin-induced injury, resulting in complete, albeit delayed, regeneration, with further enhancement of the satellite cell population. Increased p38c phosphorylation accompanied the absence of p38a, and inhibition of p38c ex vivo substantially decreased the myogenic defect. We have used genomewide transcriptome analysis to characterize the changes in expression that occur between resting and regenerating muscle, and the influence p38a has on these expression profiles. This study provides novel evidence for the fundamental role of p38a in adult muscle homeostasis in vivo.

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Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity

et al. 2017

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Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation

Cited by 14 publications

References 1 publication

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity

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