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TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens Mus

PROVIDER: GSE207170 | GEO | 2023/03/20

REPOSITORIES: GEO

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TWIST2-mediated chromatin remodeling promotes fusion-negative rhabdomyosarcoma.

Project description:Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children that resembles developing skeletal muscle. Unlike normal muscle cells, RMS cells fail to differentiate despite expression of the myogenic determination protein MYOD. The TWIST2 transcription factor is frequently overexpressed in fusion-negative RMS (FN-RMS). TWIST2 blocks differentiation by inhibiting MYOD activity in myoblasts, but its role in FN-RMS pathogenesis is incompletely understood. Here, we show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo terminal myogenesis. TWIST2 knockdown also substantially reduces tumor growth in a mouse xenograft model of FN-RMS. Mechanistically, TWIST2 controls H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers SMARCA4 and CHD3 to activate growth-related target genes and repress myogenesis-related target genes. These findings provide insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the potential of suppressing TWIST2-regulated pathways to treat FN-RMS.

| S-EPMC10146891 | biostudies-literature

TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma [ChIP-seq]

Project description: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.

2023-03-20 | GSE207165 | GEO