Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage
Summary: Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, the chief oncogene PAX3-FOXO1 is driven by a translocated FOXO1 super enhan...
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doaj-aa45c6a707d74cc38c9634ee326952452020-11-25T03:17:19ZengElsevieriScience2589-00422020-05-01235Miswired Enhancer Logic Drives a Cancer of the Muscle LineageBerkley E. Gryder0Marco Wachtel1Kenneth Chang2Osama El Demerdash3Nicholas G. Aboreden4Wardah Mohammed5Winston Ewert6Silvia Pomella7Rossella Rota8Jun S. Wei9Young Song10Benjamin Z. Stanton11Beat Schäfer12Christopher R. Vakoc13Javed Khan14Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Corresponding authorUniversity Children's Hospital, Zurich, SwitzerlandCold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USACold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USAGenetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USAGenetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USABiologic Institute, Redmond, WA, USADepartment of Oncohematology, Ospedale Pediatrico Bambino Gesu' Research Institute, IRCCS, Rome, ItalyDepartment of Oncohematology, Ospedale Pediatrico Bambino Gesu' Research Institute, IRCCS, Rome, ItalyGenetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USAGenetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USACenter for Childhood Cancer & Blood Diseases, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USAUniversity Children's Hospital, Zurich, SwitzerlandCold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USAGenetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Corresponding authorSummary: Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, the chief oncogene PAX3-FOXO1 is driven by a translocated FOXO1 super enhancer (SE) restricted to a late stage of myogenesis. Using chromatin conformation capture techniques, we demonstrate that the extensive FOXO1 cis-regulatory domain interacts with PAX3. Furthermore, RNA sequencing and chromatin immunoprecipitation sequencing data in tumors bearing rare PAX translocations implicate enhancer miswiring across all fusion-positive tumors. HiChIP of H3K27ac showed connectivity between the FOXO1 SE, additional intra-domain enhancers, and the PAX3 promoter. We show that PAX3-FOXO1 transcription is diminished when this network of enhancers is ablated by CRISPR. Our data reveal a hijacked enhancer network that disrupts the stepwise CR TF logic of normal skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an “infinite loop” enhancer logic that locks rhabdomyosarcoma in an undifferentiated stage.http://www.sciencedirect.com/science/article/pii/S2589004220302881Biological SciencesChromosome OrganizationMolecular Mechanism of Gene RegulationCancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Berkley E. Gryder Marco Wachtel Kenneth Chang Osama El Demerdash Nicholas G. Aboreden Wardah Mohammed Winston Ewert Silvia Pomella Rossella Rota Jun S. Wei Young Song Benjamin Z. Stanton Beat Schäfer Christopher R. Vakoc Javed Khan |
spellingShingle |
Berkley E. Gryder Marco Wachtel Kenneth Chang Osama El Demerdash Nicholas G. Aboreden Wardah Mohammed Winston Ewert Silvia Pomella Rossella Rota Jun S. Wei Young Song Benjamin Z. Stanton Beat Schäfer Christopher R. Vakoc Javed Khan Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage iScience Biological Sciences Chromosome Organization Molecular Mechanism of Gene Regulation Cancer |
author_facet |
Berkley E. Gryder Marco Wachtel Kenneth Chang Osama El Demerdash Nicholas G. Aboreden Wardah Mohammed Winston Ewert Silvia Pomella Rossella Rota Jun S. Wei Young Song Benjamin Z. Stanton Beat Schäfer Christopher R. Vakoc Javed Khan |
author_sort |
Berkley E. Gryder |
title |
Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage |
title_short |
Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage |
title_full |
Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage |
title_fullStr |
Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage |
title_full_unstemmed |
Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage |
title_sort |
miswired enhancer logic drives a cancer of the muscle lineage |
publisher |
Elsevier |
series |
iScience |
issn |
2589-0042 |
publishDate |
2020-05-01 |
description |
Summary: Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, the chief oncogene PAX3-FOXO1 is driven by a translocated FOXO1 super enhancer (SE) restricted to a late stage of myogenesis. Using chromatin conformation capture techniques, we demonstrate that the extensive FOXO1 cis-regulatory domain interacts with PAX3. Furthermore, RNA sequencing and chromatin immunoprecipitation sequencing data in tumors bearing rare PAX translocations implicate enhancer miswiring across all fusion-positive tumors. HiChIP of H3K27ac showed connectivity between the FOXO1 SE, additional intra-domain enhancers, and the PAX3 promoter. We show that PAX3-FOXO1 transcription is diminished when this network of enhancers is ablated by CRISPR. Our data reveal a hijacked enhancer network that disrupts the stepwise CR TF logic of normal skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an “infinite loop” enhancer logic that locks rhabdomyosarcoma in an undifferentiated stage. |
topic |
Biological Sciences Chromosome Organization Molecular Mechanism of Gene Regulation Cancer |
url |
http://www.sciencedirect.com/science/article/pii/S2589004220302881 |
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