Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage

Gryder, B. E., Wachtel, M., Chang, K., El Demerdash, O., Aboreden, N.G., Mohammed, W., Ewert, W., Pomella, S., Rota, R., Wei, J.S., Song, Y., Stanton, B. Z., Schafer, B., Vakoc, C.R., Khan, J. (May 2020) Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage. iScience, 23 (5). p. 101103. ISSN 2589-0042

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Abstract

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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA translocation bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > cis-regulatory elements bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
CSHL Authors:	Vakoc, Christopher R. Chang, Kenneth Demerdash, Osama E.
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Vakoc lab CSHL Cancer Center Program
Depositing User:	Adrian Gomez
Date:	22 May 2020
Date Deposited:	18 May 2020 16:10
Last Modified:	13 Feb 2024 21:20
PMCID:	PMC7226896
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39467

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