Transcriptional elongation control of hypoxic response

Proc Natl Acad Sci U S A. 2024 Apr 9;121(15):e2321502121. doi: 10.1073/pnas.2321502121. Epub 2024 Apr 2.


The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation.

Keywords: RNA polymerase II; chromatin; epigenetic mechanisms; gene expression; transcription.

MeSH terms

  • Bromodomain Containing Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism
  • Cyclin-Dependent Kinases / metabolism
  • Gene Expression Regulation
  • Humans
  • Hypoxia
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Phosphorylation
  • Positive Transcriptional Elongation Factor B / genetics
  • Positive Transcriptional Elongation Factor B / metabolism
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcription, Genetic


  • Transcription Factors
  • Nuclear Proteins
  • Cyclin-Dependent Kinases
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II
  • Positive Transcriptional Elongation Factor B
  • BRD4 protein, human
  • Bromodomain Containing Proteins
  • Cell Cycle Proteins