Twist2 amplification in rhabdomyosarcoma represses myogenesis and promotes oncogenesis by redirecting MyoD DNA binding
- Stephen Li1,2,3,
- Kenian Chen4,5,
- Yichi Zhang1,2,3,
- Spencer D. Barnes6,
- Priscilla Jaichander1,2,3,
- Yanbin Zheng7,8,
- Mohammed Hassan7,8,
- Venkat S. Malladi6,
- Stephen X. Skapek7,8,
- Lin Xu2,4,5,
- Rhonda Bassel-Duby1,2,3,
- Eric N. Olson1,2,3 and
- Ning Liu1,2,3
- 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 2Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 3Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 4Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 5Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 6Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 7Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 8Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
- Corresponding authors: eric.olson{at}utsouthwestern.edu, ning.liu{at}utsouthwestern.edu
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
- skeletal muscle
- bHLH
- chromosome amplification
- dedifferentiation
- histone modification
- rhabdomyosarcoma
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.324467.119.
- Received January 16, 2019.
- Accepted March 25, 2019.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
