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Chemical genomics reveals histone deacetylases are required for core regulatory transcription

Berkley E Gryder1, Lei Wu2, Girma M Woldemichael3

  • 1Genetics Branch, NCI, NIH, Bethesda, MD, 20892, USA.

Nature Communications
|July 10, 2019
PubMed

Insights

Chemical probes targeting the acetylation axis, not methylation, disrupt cancer cell transcription. Histone deacetylases (HDACs) 1, 2, and 3 are essential for core regulatory transcription, offering new cancer treatment strategies.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Chemical Genetics

Background:

  • Core regulatory (CR) transcription factors (TFs) drive cell identity and are regulated by super enhancers (SEs).
  • Targeting CR circuitry with drugs is a key strategy for cancer treatment.
  • Alveolar rhabdomyosarcoma, driven by PAX3-FOXO1, serves as a model for cancer cell dependence on CR transcription.

Purpose of the Study:

  • To screen for epigenetic chemical probes that can differentiate between SE-driven and constitutive transcription.
  • To identify specific epigenetic mechanisms regulating CR transcription in cancer.

Main Methods:

  • Utilized chemical genetics for systematic screening of chemical matter.
  • Employed a screen for epigenetic chemical probes targeting transcription.
  • Investigated histone deacetylase (HDAC) isoform contributions using selective inhibitors, including a novel HDAC3 inhibitor (LW3).

Main Results:

  • Chemical probes targeting the acetylation axis, but not the methylation axis, selectively disrupted CR transcription.
  • Histone deacetylases (HDACs) were found to be essential for CR TF transcription.
  • Co-inhibition of HDAC1, HDAC2, and HDAC3 halted CR transcription, leading to hyper-accessible CR TF sites and disrupted chromatin looping.

Conclusions:

  • Epigenetic regulation via acetylation is crucial for maintaining cancer-driving CR transcription.
  • HDAC1, HDAC2, and HDAC3 are co-essential for CR transcription and represent potential therapeutic targets.
  • Disrupting this HDAC network offers a novel approach to halt cancer transcription and chromatin organization.

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