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Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven

E Donato1, O Croci1, A Sabò1

  • 1Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.

Leukemia
|July 23, 2016
PubMed

Insights

Bromodomain and extraterminal motif (BET) inhibitors like JQ1 selectively impact gene transcription by affecting transcriptional elongation, not Myc downregulation. This reveals BET proteins

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Bromodomain and extraterminal motif (BET) proteins, including BRD4, are key epigenetic regulators.
  • BET inhibitors show promise in cancer therapy, often linked to Myc downregulation.
  • The precise mechanism of BET inhibitor action, particularly JQ1, requires further elucidation.

Purpose of the Study:

  • To investigate the mechanism of action of the BET inhibitor JQ1 in B-cell tumors.
  • To determine the relationship between BRD4 eviction, gene transcription, and Myc regulation.
  • To identify factors determining JQ1 sensitivity in gene expression.

Main Methods:

  • Utilized B-cell tumors as a model system.
  • Administered JQ1, a widely used BET inhibitor.
  • Analyzed BRD4 chromatin occupancy, gene transcription, and RNA Polymerase II (RNAPol2) recruitment.

Main Results:

  • JQ1 induced widespread BRD4 eviction from chromatin but selectively affected a subset of genes.
  • JQ1's effects were unlinked to Myc downregulation; sensitive genes were enriched for Myc/E2F targets with high basal transcription.
  • JQ1 inhibited transcriptional elongation, with sensitive genes unable to compensate via enhanced RNAPol2 recruitment.

Conclusions:

  • BRD4 plays a crucial role in supporting transcriptional elongation, particularly for highly expressed genes.
  • Selective gene transcription inhibition by JQ1 arises from the inability of sensitive genes to recruit compensatory RNAPol2.
  • BET proteins are critical for maintaining transcriptional elongation, explaining selective effects of elongation inhibitors.

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