Nature genetics, 2019-12, Vol.51 (12), p.1714-1722
2019
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma
- Ist Teil von
- Nature genetics, 2019-12, Vol.51 (12), p.1714-1722
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036eISSN: 1546-1718DOI: 10.1038/s41588-019-0534-4Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6886578
- Format
- –
- Schlagworte
- Acetylation, Architecture, Benzamides - pharmacology, Binding sites, Cancer, Cell Line, Tumor, Chromatin Immunoprecipitation, Circuits, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR, DNA binding proteins, DNA-directed RNA polymerase, Enhancer Elements, Genetic, Enhancers, Epigenetics, Forkhead Box Protein O1 - genetics, Forkhead Box Protein O1 - metabolism, Gene Expression Regulation, Neoplastic - drug effects, Gene Regulatory Networks, Genes, Genetic aspects, Genetic transcription, Genomes, Histone Deacetylases - genetics, Histone Deacetylases - metabolism, Histones, Histones - genetics, Histones - metabolism, Humans, Kinases, Phenotypes, Pyridines - pharmacology, Rhabdomyosarcoma, Rhabdomyosarcoma - genetics, Ribonucleic acid, RNA, RNA polymerase, RNA polymerase II, RNA Polymerase II - genetics, RNA Polymerase II - metabolism, RNA Stability, Scientific equipment and supplies industry, Single-Cell Analysis, SOXE Transcription Factors - genetics, Stem cells, Transcription factors, Transcription Factors - genetics, Tumors