Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma

Nat Genet. 2019 Dec;51(12):1714-1722. doi: 10.1038/s41588-019-0534-4. Epub 2019 Nov 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Benzamides
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Histones
  • Pyridines
  • SOX8 protein, human
  • SOXE Transcription Factors
  • Transcription Factors
  • entinostat
  • RNA Polymerase II
  • Histone Deacetylases