Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Core regulatory transcription factors (CR TFs) control cell identity genes via super-enhancers (SEs) and are vital in cancer.
• Rhabdomyosarcoma (RMS) pathogenesis involves dysregulated CR TFs and SEs.

Purpose of the Study:

• To define the core regulatory circuitry of rhabdomyosarcoma.
• To identify CR TF dependencies in RMS.
• To investigate the impact of histone modifications on SE architecture and CR TF transcription.

Main Methods:

• Defined RMS core regulatory circuitry.
• Utilized absolute quantification of architecture (AQuA) HiChIP.
• Analyzed histone acetylation and deacetylation levels at SEs.
• Assessed RNA polymerase II (RNA Pol II) and BRD4 condensate dynamics.

Main Results:

• Identified critical CR TF dependencies in rhabdomyosarcoma.
• Observed paradoxically high histone acetylation and deacetylation at CR TF-bound SEs.
• Demonstrated that hyperacetylation halts CR TF transcription by disrupting SE architecture and removing RNA Pol II.
• Showed aberrant spreading of histone acetylation and erosion of native SE contacts.

Conclusions:

• Rhabdomyosarcoma CR TF transcription is halted by hyperacetylation.
• SE architecture is compromised by aberrant histone modifications.
• Balancing histone modification states is essential for maintaining SE architecture and CR TF transcription in an SE-specific manner.