Histone Hyperacetylation Disrupts Core Gene Regulatory Architecture in Rhabdomyosarcoma

Overview

Journal Nat Genet

Specialty Genetics

Date 2019 Dec 1

PMID 31784732

Citations 92

Authors

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

Affiliations

Soon will be listed here.

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.

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