Gryder, B. E., Pomella, S., Sayers, C., Wu, X. S., Song, Y., Chiarella, A. M., Bagchi, S., Chou, H. C., Sinniah, R. S., Walton, A., Wen, X., Rota, R., Hathaway, N. A., Zhao, K., Chen, J., Vakoc, C. R., Shern, J. F., Stanton, B. Z., Khan, J. (December 2019) Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma. Nat Genet, 51 (12). pp. 1714-1722. ISSN 1061-4036 (Public Dataset)
Abstract
Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma and identify critical CR TF dependencies. These CR TFs build SEs that have the highest levels of histone acetylation, yet paradoxically the same SEs also harbor the greatest amounts of histone deacetylases. We find that hyperacetylation selectively halts CR TF transcription. To investigate the architectural determinants of this phenotype, we used absolute quantification of architecture (AQuA) HiChIP, which revealed erosion of native SE contacts, and aberrant spreading of contacts that involved histone acetylation. Hyperacetylation removes RNA polymerase II (RNA Pol II) from core regulatory genetic elements, and eliminates RNA Pol II but not BRD4 phase condensates. This study identifies an SE-specific requirement for balancing histone modification states to maintain SE architecture and CR TF transcription.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > RNA polymerase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > histone deacetylase |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Adrian Gomez |
| Date: | December 2019 |
| Date Deposited: | 18 Dec 2019 17:51 |
| Last Modified: | 05 Nov 2020 16:46 |
| PMCID: | PMC6886578 |
| Related URLs: | |
| Dataset ID: |
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| URI: | https://repository.cshl.edu/id/eprint/38791 |
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