The transcription factor Lef1 switches partners from β-catenin to Smad3 during muscle stem cell quiescence

Aloysius, Ajoy; DasGupta, Ramanuj; Dhawan, Jyotsna

doi:10.1126/scisignal.aan3000

Cited by 37 publications

(31 citation statements)

References 93 publications

(130 reference statements)

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“…Earlier, we showed that quiescent myoblasts in culture display a distinct transcriptional profile, with altered signaling modules, in particular, enhanced Wnt-TCF signaling [12,23]. Interestingly, a number of ciliumassociated genes showed increased expression in G0.…”

Section: Primary Cilia Are Dynamically Regulated During the Cell Cyclmentioning

confidence: 84%

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The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

Venugopal

Ghosh

Gala

et al. 2020

BMC Mol and Cell Biol

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Background: Reversible cell cycle arrest (quiescence/G0) is characteristic of adult stem cells and is actively controlled at multiple levels. Quiescent cells also extend a primary cilium, which functions as a signaling hub. Primary cilia have been shown to be important in multiple developmental processes, and are implicated in numerous developmental disorders. Although the association of the cilium with G0 is established, the role of the cilium in the control of the quiescence program is still poorly understood. Results: Primary cilia are dynamically regulated across different states of cell cycle exit in skeletal muscle myoblasts: quiescent myoblasts elaborate a primary cilium in vivo and in vitro, but terminally differentiated myofibers do not. Myoblasts where ciliogenesis is ablated using RNAi against a key ciliary assembly protein (IFT88) can exit the cell cycle but display an altered quiescence program and impaired self-renewal. Specifically, the G0 transcriptome in IFT88 knockdown cells is aberrantly enriched for G2/M regulators, suggesting a focused repression of this network by the cilium. Cilium-ablated cells also exhibit features of activation including enhanced activity of Wnt and mitogen signaling and elevated protein synthesis via inactivation of the translational repressor 4E-BP1. Conclusions: Taken together, our results show that the primary cilium integrates and dampens proliferative signaling, represses translation and G2/M genes, and is integral to the establishment of the quiescence program.

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Section: Primary Cilia Are Dynamically Regulated During the Cell Cyclmentioning

confidence: 84%

“…All assays were performed as described on stable clones expressing either the Super8X-TOP-flash (TCF site) construct, TFC-1, or the FOP-flash (mutated TCF site) construct [59], FFC-15. TFC-1 and FFC-15 clones were derived earlier [12,23].…”

Section: Luciferase Reporter Assays For Testing Wnt Pathway Activitymentioning

confidence: 99%

The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

Venugopal

Ghosh

Gala

et al. 2020

BMC Mol and Cell Biol

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“…(Transforming growth factor beta-3) itself, TGF-beta receptor type-2 (TGFBR2) a receptor for the TGF-beta ligands TGFB1, TGFB2 & TGFB3 as well as; LEF1, that is associated with WNT-TCF/LEF and TGF-Beta-SMAD3 signalling in controlling muscle stem cell proliferation and self-renewal 64 . Finally, MECOM (alias EVI-1) has been demonstrated to play a role in growth regulation via TGF-beta/SMAD signalling 65 .…”

Section: Kegg Cancermentioning

confidence: 99%

Comparative Transcriptome and Methylome Analysis in Human Skeletal Muscle Anabolism, Hypertrophy and Epigenetic Memory

Turner

Seaborne

Sharples

2018

Preprint

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38Transcriptome wide changes in human skeletal muscle after acute (anabolic) and chronic resistance exercise 39 (RE) induced hypertrophy have been extensively determined in the literature. We have also recently 40 undertaken DNA methylome analysis (850,000 + CpG sites) in human skeletal muscle after acute and 41 chronic RE, detaining and retraining, where we identified an association between DNA methylation in an 42 epigenetic memory of exercise induced skeletal muscle hypertrophy. However, it is currently unknown as to 43 whether all the genes identified in the transcriptome studies to date are also epigenetically regulated at the 44 DNA level after acute, chronic or repeated RE exposure. We therefore aimed to undertake large scale 45 bioinformatical analysis by pooling the publicly available transcriptome data after acute (110 samples) and 46 chronic RE (181 samples) and comparing these large data sets with our genome-wide DNA methylation 47 analysis in human skeletal muscle after acute and chronic RE, detraining and retraining. Indeed, after acute 48 RE we identified 866 up-and 936 down-regulated genes at the expression level, with 270 (out of the 866 up-49 regulated) identified as being hypomethylated, and 216 (out of 936 downregulated) as hypermethylated. 50After chronic RE we identified 2,018 up-and 430 down-regulated genes with 592 (out of 2,018 upregulated) 51 identified as being hypomethylated and 98 (out of 430 genes downregulated) as hypermethylated. After 52 KEGG pathway analysis, genes associated with 'cancer' pathways were significantly enriched in both 53 bioinformatic analysis of the pooled transcriptome and methylome data after both acute and chronic RE. 54 This resulted in 23 (out of 69) and 28 (out of 49) upregulated and hypomethylated and 12 (out of 37) and 2 55 (out of 4) downregulated and hypermethylated 'cancer' genes following acute and chronic RE respectively. 56Within skeletal muscle tissue, these 'cancer' genes predominant functions were associated with matrix/ actin 57 structure and remodelling, mechano-transduction (including PTK2/Focal Adhesion Kinase and 58 Phospholipase D-following chronic RE only), TGF-beta signalling and protein synthesis (GSK3B after 59 acute RE only). Interestingly, 51 genes were also identified to be up/downregulated in both the acute and 60 chronic RE pooled transcriptome analysis as well as significantly hypo/hypermethylated after acute RE, 61 chronic RE, detraining and retraining. Five genes; FLNB, MYH9, SRGAP1, SRGN, ZMIZ1 demonstrated 62 increased gene expression in the acute and chronic RE transcriptome and also demonstrated 63 hypomethylation in these conditions. Importantly, these 5 genes demonstrated retained hypomethylation 64 even during detraining (following training induced hypertrophy) when exercise was ceased and lean mass 65 returned to baseline (pre-training) levels, identifying them as potential epigenetic memory genes. 66 Importantly, for the first time across the transcriptome and epigenome combined, this study identifies novel 67 diffe...

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“…TGFβ signaling has been shown, mainly in vitro , to negatively regulate myoblast differentiation through functional repression of the myogenic regulatory factors Myod1 21 and Myogenin 22 . However, TGFβ signaling has broader function in muscle cells, including quiescence 23 and activation 24 and the impact of TGFβ in syncytia formation has never been investigated. This lack in our knowledge mainly comes from the fact that the primary effects of TGFβ over-expression in skeletal muscles are development of endomysial fibrosis, due to its role as a potent growth factor for connective tissue cells 25,26 .…”

Section: Introductionmentioning

confidence: 99%

TGFβ signaling curbs cell fusion and muscle regeneration

Girardi

Taleb

Giordani

et al. 2019

Preprint

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SummaryFusion of muscle progenitor cells is necessary for skeletal muscle development and repair. Cell fusion is a multistep process involving cell migration, adhesion, membrane remodeling and actin-nucleation pathways to generate multinucleated myotubes. While the cellular and molecular mechanisms promoting muscle cell fusion have been intensely investigated in recent years, molecular brakes restraining cell–cell fusion events to control syncytia formation have remained elusive. Here, we show that transforming growth factor beta (TGFβ) signaling is active in adult muscle cells throughout the fusion process and reduce muscle cell fusion independently of the differentiation step. In contrast, inhibition of TGFβ signaling enhances cell fusion and promotes branching between myotubes. Pharmacological modulation of the pathway in vivo perturbs muscle regeneration after injury. Exogenous addition of TGFβ protein results in a loss of muscle function while inhibition of the TGFβ pathway induces the formation of giant myofibres. Transcriptome analyses and functional assays revealed that TGFβ acts on actin dynamics and reduce cell spreading through modulation of actin-based protrusions. Together our results reveal a signaling pathway that limits mammalian myoblast fusion and add a new level of understanding to the molecular regulation of myogenesis.

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The transcription factor Lef1 switches partners from β-catenin to Smad3 during muscle stem cell quiescence

Cited by 37 publications

References 93 publications

The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

Comparative Transcriptome and Methylome Analysis in Human Skeletal Muscle Anabolism, Hypertrophy and Epigenetic Memory

TGFβ signaling curbs cell fusion and muscle regeneration

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