Abstract
SummaryCore 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.
Highlights
Control of the expression of the core regulatory transcription factors (CR TFs) that guide developmental decision making are directed by logical enhancer elements (Boyer et al, 2005; Chen et al, 2008; Lee and Young, 2013; Vermunt et al, 2019)
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
Summary
Control of the expression of the core regulatory transcription factors (CR TFs) that guide developmental decision making are directed by logical enhancer elements (Boyer et al, 2005; Chen et al, 2008; Lee and Young, 2013; Vermunt et al, 2019). These genomic elements, when heavily activated, become super enhancers (SEs) with unusually large deposits of active histone marks, chromatin regulators, and transcriptional coactivators (Hnisz et al, 2013). We test the hypothesis that the chromosomal translocation event resulted in novel enhancer/ promoter interactions to maintain robust expression of the oncogenic fusion protein in FP-RMS
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
