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| Status |
Public on Mar 20, 2023 |
| Title |
TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma [RNA-seq Xenograft] |
| Organism |
Mus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Sarcomas are derailed in pathways that specify mesenchymal lineages during embryogenesis, causing tumor cells to stall at early stages of differentiation. Among them, rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of skeletal muscle origin. A key feature of RMS is their inability to terminally differentiate despite the high expression of master myogenic regulator MYOD. The bHLH transcription factor TWIST2, which governs mesenchymal stem cell identity and restricts myogenesis, is overexpressed in patient fusion-negative RMS (FN-RMS) tumors. We show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo myogenic differentiation, thereby reducing the growth of FN-RMS xenograft tumors. ChIP-seq analysis revealed that most TWIST2-mediated gene regulation occurs independent of changes in MYOD binding in FN-RMS cells. Instead, TWIST2 controls the deposition of H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers, SMARCA4 and CHD3, to activate growth-related and repress myogenesis-related TWIST2 target genes. Our findings provide new insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the clinical potential of reversing the TWIST2-regulated phenotype.
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| Overall design |
RNA was isolated from Doxycycline (Dox)-inducible shTWIST2 RD xenograft tumors treated with +Dox (TWIST2 KD) or -Dox (Control) for 52 days. Stranded mRNA-seq was performed to profile gene expression changes upon TWIST2 knockdown.
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| Contributor(s) |
Shah A, Guo L, Chen K, Xu L, Liu N, Olson EN |
| Citation(s) |
37115930 |
| |
| Submission date |
Jun 29, 2022 |
| Last update date |
May 12, 2023 |
| Contact name |
Lei Guo |
| E-mail(s) |
[email protected]
|
| Phone |
7018859551
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| Organization name |
University of Texas Southwestern Medical Center
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| Department |
Department of Population and Data Sciences
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| Lab |
Lin Xu
|
| Street address |
5323 Harry Hines Blvd
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| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75206 |
| Country |
USA |
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| Platforms (1) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE207170 |
TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma. |
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| Relations |
| BioProject |
PRJNA854058 |
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