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Genes Dev. 2019 Jun 1;33(11-12):626-640. doi: 10.1101/gad.324467.119. Epub 2019 Apr 11.

Twist2 amplification in rhabdomyosarcoma represses myogenesis and promotes oncogenesis by redirecting MyoD DNA binding.

Li S1,2,3, Chen K4,5, Zhang Y1,2,3, Barnes SD6, Jaichander P1,2,3, Zheng Y7,8, Hassan M7,8, Malladi VS6, Skapek SX7,8, Xu L2,4,5, Bassel-Duby R1,2,3, Olson EN1,2,3, Liu N1,2,3.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
3
Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
4
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
5
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
6
Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
7
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
8
Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer composed of myoblast-like cells. Recently, we discovered a unique muscle progenitor marked by the expression of the Twist2 transcription factor. Genomic analyses of 258 RMS patient tumors uncovered prevalent copy number amplification events and increased expression of TWIST2 in fusion-negative RMS. Knockdown of TWIST2 in RMS cells results in up-regulation of MYOGENIN and a decrease in proliferation, implicating TWIST2 as an oncogene in RMS. Through an inducible Twist2 expression system, we identified Twist2 as a reversible inhibitor of myogenic differentiation with the remarkable ability to promote myotube dedifferentiation in vitro. Integrated analysis of genome-wide ChIP-seq and RNA-seq data revealed the first dynamic chromatin and transcriptional landscape of Twist2 binding during myogenic differentiation. During differentiation, Twist2 competes with MyoD at shared DNA motifs to direct global gene transcription and repression of the myogenic program. Additionally, Twist2 shapes the epigenetic landscape to drive chromatin opening at oncogenic loci and chromatin closing at myogenic loci. These epigenetic changes redirect MyoD binding from myogenic genes toward oncogenic, metabolic, and growth genes. Our study reveals the dynamic interplay between two opposing transcriptional regulators that control the fate of RMS and provides insight into the molecular etiology of this aggressive form of cancer.

KEYWORDS:

bHLH; chromosome amplification; dedifferentiation; histone modification; rhabdomyosarcoma; skeletal muscle

PMID:
30975722
PMCID:
PMC6546057
[Available on 2019-12-01]
DOI:
10.1101/gad.324467.119
[Indexed for MEDLINE]

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