Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma
| Autor: | Hsien-Chao Chou, Anna M. Chiarella, Jiji Chen, Javed Khan, Sukriti Bagchi, Xinyu Wen, Ranu S Sinniah, Ashley Walton, Nathaniel A. Hathaway, Silvia Pomella, Young Min Song, Jack F. Shern, Xiaoli S. Wu, Christopher R. Vakoc, Benjamin Z. Stanton, Berkley E. Gryder, Keji Zhao, Rossella Rota, Carly M. Sayers |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
BRD4
Chromatin Immunoprecipitation Pyridines RNA Stability RNA polymerase II Settore MED/05 Article Histone Deacetylases Histones 03 medical and health sciences 0302 clinical medicine Transcription (biology) Cell Line Tumor Rhabdomyosarcoma Genetics Humans Clustered Regularly Interspaced Short Palindromic Repeats Gene Regulatory Networks Transcription factor 030304 developmental biology Regulation of gene expression 0303 health sciences biology Forkhead Box Protein O1 SOXE Transcription Factors Acetylation Cell biology Gene Expression Regulation Neoplastic Histone Enhancer Elements Genetic Benzamides biology.protein Histone deacetylase RNA Polymerase II Single-Cell Analysis Chromatin immunoprecipitation 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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