Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage

iScience

Christopher R. Vakoc¹  Marco Wachtel²  Silvia Pomella³  Beat Schäfer⁴  Osama El Demerdash⁵  Nicholas G. Aboreden⁵  Jun S. Wei⁶  Rossella Rota⁶  Young Song⁷  Wardah Mohammed⁷  Berkley E. Gryder⁷  Winston Ewert⁷  Benjamin Z. Stanton⁷  Kenneth Chang⁸  Javed Khan⁸ 

[1] Blood Diseases, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA;Corresponding author;Biologic Institute, Redmond, WA, USA;;Center for Childhood Cancer &Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA;Department of Oncohematology, Ospedale Pediatrico Bambino Gesu' Research Institute, IRCCS, Rome, Italy;Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA;University Children's Hospital, Zurich, Switzerland;

关键词: Biological Sciences;    Chromosome Organization;    Molecular Mechanism of Gene Regulation;    Cancer;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown