An HMGA2-IGF2BP2 Axis Regulates Myoblast Proliferation and Myogenesis

Li, Zhizhong; Gilbert, Jason A.; Zhang, Yunyu; Zhang, Minsi; Qiu, Qiong; Ramanujan, Krishnan; Shavlakadze, Tea; Eash, John K.; Scaramozza, Annarita; Goddeeris, Matthew M.; Kirsch, David G.; Campbell, Kevin P.; Brack, Andrew S.; Glass, David J.

doi:10.1016/j.devcel.2012.10.019

Cited by 141 publications

(131 citation statements)

References 39 publications

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“…Indeed, Hmga2 knockout mice display skeletal muscle hypotrophy due to impaired myoblast proliferation, whereas Dicer knockout mice show decreased skeletal muscle mass with abnormal myofiber morphology, partly as a result of increased apoptosis in muscle cells (Li et al, 2012; O'Rourke et al, 2007). In line with a role in promoting myoblast proliferation or survival, both Hmga2 and Dicer are highly expressed in proliferating myoblasts and their expression declines upon differentiation (Li et al, 2012; O'Rourke et al, 2007; Sago et al, 2004). We find that both Hmga2 and Dicer mRNA levels decrease in C2C12 myoblasts transfected with simH19 or let-7 (Figure 6B, 2 nd and 3 rd columns from left, compare green and purple bars with blue bars), consistent with Hmga2 and Dicer being additional downstream effectors of H19/let-7-mediated regulation.…”

Section: Resultsmentioning

confidence: 99%

The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs

et al. 2013

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SUMMARY Abundantly expressed in fetal tissues and adult muscle, the developmentally regulated H19 long noncoding RNA (lncRNA) has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic, despite the recent implication of its encoded miR675 in limiting placental growth. We noted that vertebrate H19 harbors both canonical and noncanonical binding sites for the let-7 family of microRNAs, which plays important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, we demonstrate that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in culture where H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Our results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs.

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Section: Resultsmentioning

confidence: 99%

The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs

et al. 2013

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“…HMGA2 is more than a simple marker of the ERMS subtype of disease; using both gain-of-function and loss-of-function assays, we identified HMGA2 as a required gene, mediating proliferation and survival of ERMS cells both in vitro and in vivo . In a parallel study, we have also shown that HMGA2 is an important factor regulating normal mouse myoblast growth and myogenesis—in normal myoblasts, HMGA2 must be downregulated in order for the differentiation process to take place (30). These studies together help to explain why the pathologic upregulation and maintenance of HMGA2 expression may presage oncogenic transformation—the differentiation stage is thereby blocked.…”

Section: Discussionmentioning

confidence: 97%

Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway

Zhang

Ramanujan

et al. 2013

Cancer Research

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Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin–like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2–IGFBP2–NRAS signaling pathway as a critical oncogenic driver in ERMS.

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“…Finally, let-7f, also upregulated in EVs, targets genes associated to transcription and membrane-associated proteins with implications in cellular reprogramming and growth, like the upregulated lin-28 homolog-B (LIN28B) 59 , high-mobility-group AT-hook-2 (HMGA2) 60 , and the insulin-like growth factor-2 mRNA binding protein-1 (IGF2BP1) 61 . Collectively, our observations suggest that EVs are potential modulators of tissue repair by reprogramming target cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA and mRNA cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells

Eirin

Riester

Zhu

et al. 2014

Gene

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Mesenchymal stromal/stem cells (MSCs) are clinically useful for cell-based therapy, but concerns regarding their ability to replicate limit their human application. MSCs release extracellular vesicles (EVs) that mediate at least in part the paracrine effects of the parental cells. To understand the molecular basis of their biological properties, we characterized the RNA cargo of EVs from porcine adipose-tissue derived MSCs. Comprehensive characterization of mRNA and miRNA gene expression using high-throughput RNA sequencing (RNA-seq) revealed that EVs are selectively enriched for distinct classes of RNAs. For example, EVs preferentially express mRNA for transcription factors (e.g. MDFIC, POU3F1, NRIP1) and genes involved in angiogenesis (e.g. HGF, HES1, TCF4) and adipogenesis (e.g. CEBPA, KLF7). EVs also express Golgi apparatus genes (ARRB1, GOLGA4) and genes involved in TGF-β signaling. In contrast, mitochondrial, calcium signaling, and cytoskeleton genes are selectively excluded from EVs, possibly because these genes remain sequestered in organelles or intracellular compartments. RNA-seq generated reads for at least 386 annotated miRNAs, but only miR148a, miR532-5p, miR378, and let-7f were enriched in EVs compared to MSCs. Gene ontology analysis indicates that these miRNA target transcription factors and genes that participate in several cellular pathways, including angiogenesis, cellular transport, apoptosis, and proteolysis. Our data suggest that EVs transport gene regulatory information to modulate angiogenesis, adipogenesis, and other cell pathways in recipient cells. These observations may contribute to development of regenerative strategies using EVs to overcome potential complications of cell-based therapy.

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An HMGA2-IGF2BP2 Axis Regulates Myoblast Proliferation and Myogenesis

Cited by 141 publications

References 39 publications

The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs

The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs

Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway

MicroRNA and mRNA cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells

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