Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma

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:	bioinformatics diseases & disorders > cancer 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 > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > RNA polymerase organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > histone bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > histone deacetylase organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Vakoc, Christopher R.
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:	02 Feb 2024 15:27
PMCID:	PMC6886578
Related URLs:	Publisher
Dataset ID:	GEO: GSE116344 Code: https://github.com/GryderArt
URI:	https://repository.cshl.edu/id/eprint/38791

Actions (login required)

Administrator's edit/view item