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Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma

ABSTRACT: Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma

PROVIDER: PRJNA865754 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20800727_1.fastq.gz	Fastqsanger.gz
	SRR20800727_2.fastq.gz	Fastqsanger.gz
	SRR20800728_1.fastq.gz	Fastqsanger.gz
	SRR20800728_2.fastq.gz	Fastqsanger.gz
	SRR20800729_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma

Project description:Rhabdomyocarcoma (RMS) contains myoblast-like cells that fail in terminal differentiation. To explore the potential defects in differentiation, we studied mRNA splicing variants in genes encoding transcription factors critical for skeletal muscle differentiation with RNA-Seq data from RMS specimens and cell lines. We identified novel exon 2 skipping form of MYOD1 and MYF5. Further study on MYODΔEx2 protein showed that it failed to robustly induce muscle-specific genes but its ectopic expression conferred a selective advantage in cultured fibroblasts and an RMS xenograft. Therefore, alternative splicing can represent a mechanism to alter the function of these two transcription factors in RMS.

2022-08-06 | GSE210475 | GEO

Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma.

Project description:Rhabdomyosarcoma (RMS) is a childhood sarcoma composed of myoblast-like cells, which suggests a defect in terminal skeletal muscle differentiation. To explore potential defects in the differentiation program, we searched for mRNA splicing variants in genes encoding transcription factors driving skeletal muscle lineage commitment and differentiation. We studied two RMS cases and identified altered splicing resulting in "skipping" the second of three exons in MYOD1. RNA-Seq data from 42 tumors and additional RMS cell lines revealed exon 2 skipping in both MYOD1 and MYF5 but not in MYF6 or MYOG. Complementary molecular analysis of MYOD1 mRNA found evidence for exon skipping in 5 additional RMS cases. Functional studies showed that so-called MYODΔEx2 protein failed to robustly induce muscle-specific genes, and its ectopic expression conferred a selective advantage in cultured fibroblasts and an RMS xenograft. In summary, we present previously unrecognized exon skipping within MYOD1 and MYF5 in RMS, and we propose that alternative splicing can represent a mechanism to alter the function of these two transcription factors in RMS.

| S-EPMC9528969 | biostudies-literature

SNAIL is a key regulator of rhabdomyosarcoma progression and myogenic differentiation

Project description:Rhabdomyosarcoma (RMS) is a frequent non-epithelial tumor of soft tissue that originates from a myogenic differentiation defect. Expression of SNAIL transcription factor is elevated in the alveolar subtype of RMS, characterized by a low myogenic differentiation status and high aggressiveness. SNAIL affects RMS metastasis by reorganization of actin cytoskeleton, regulation of ezrin expression and chemotaxis to HGF and SDF-1. The differentiation of human RMS diminishes SNAIL level. SNAIL silencing completely abolishes the growth of human RMS xenotransplants. SNAIL inhibits myogenic differentiation of RMS by binding to the MYF5 promoter, suppressing its expression, displacing MYOD from canonical to alternative E-box sequences and regulating myomiRs expression. SNAIL silencing allows the re-expression of MYF5 and canonical MYOD binding, promoting RMS cell myogenic differentiation. These novel results open potential avenues for the development of innovative therapeutic strategies based on SNAIL silencing.

2020-07-14 | PXD006711 | Pride

Cotranscriptional exon skipping in the genotoxic stress response

Project description:Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin, inhibit the interaction between EWS, an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene encoding the main p53 ubiquitin-ligase. This reversible exon skipping participates in the timely regulation of MDM2 expression, and may contribute to the accumulation of p53 during stress exposure and its rapid shut off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to camptothecin and EWS/YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, resulting in widespread exon skipping and playing a central role in the genotoxic stress response. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x control_6 hours; 3 x camptothecin_6 hours.

2010-06-09 | E-GEOD-21840 | biostudies-arrayexpress

MEK inhibition profoundly reprograms myogenic super enhancers in mutant-RAS driven Rhabdomyosarcoma

Project description:Trametinib-treated rhabdomyosarcoma cells undergo transcriptional reprogramming akin to myogenic differentiation. This reprogramming is induced by loss of ERK-mediated inhibition of MYOG expression. Restoration of MYOG allows establishment of super-enhancers at genes expressed by terminally differentiated myotubes. Our findings demonstrate that aberrant MAP kinase activity blocks differentiation in rhabdomyosarcoma and highlight trametinib as a potential therapeutic for RAS-mutated rhabdomyosarcoma.

2018-04-01 | GSE85169 | GEO

TRPS1 impairs myogenic differentiation in embryonal rhabdomyosarcoma

Project description:TRPS1 impairs myogenic differentiation in embryonal rhabdomyosarcoma

| PRJNA810873 | ENA

MEK inhibition rewires enhancer landscapes in RAS-driven Rhabdomyosarcoma to unlock a myogenic differentation block

2018-04-01 | GSE85170 | GEO

PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors [RNA-seq]

Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

2023-09-30 | GSE241645 | GEO

PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors [Cut&Run]

2023-09-30 | GSE241644 | GEO

PAX3-FOXO1 expression in endothelial progenitors dictates myogenic reprogramming and rhabdomyosarcoma identity[Hi-C]

Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a novel FP-RMS mouse model driven by P3F expression and CDKN2A loss in endothelial cells. Additionally, we show that P3F expression in p53 null human iPSCs blocks endothelial directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

2023-09-30 | GSE218254 | GEO

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