Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma

Berkley E Gryder, Silvia Pomella, Carly Sayers, Xiaoli S Wu, Young Song, Anna M Chiarella, Sukriti Bagchi, Hsien-Chao Chou, Ranu S Sinniah, Ashley Walton, Xinyu Wen, Rossella Rota, Nathaniel A Hathaway, Keji Zhao, Jiji Chen, Christopher R Vakoc, Jack F Shern, Benjamin Z Stanton, Javed Khan

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1714-1722
Number of pages9
JournalNature Genetics
Volume51
Issue number12
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Acetylation
  • Benzamides/pharmacology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Enhancer Elements, Genetic
  • Forkhead Box Protein O1/genetics
  • Gene Expression Regulation, Neoplastic/drug effects
  • Gene Regulatory Networks
  • Histone Deacetylases/genetics
  • Histones/genetics
  • Humans
  • Pyridines/pharmacology
  • RNA Polymerase II/genetics
  • RNA Stability
  • Rhabdomyosarcoma/genetics
  • SOXE Transcription Factors/genetics
  • Single-Cell Analysis
  • Transcription Factors/genetics

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