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. 2024 Apr 9;121(15):e2321502121.
doi: 10.1073/pnas.2321502121. Epub 2024 Apr 2.

Transcriptional elongation control of hypoxic response

Shimaa Hassan AbdelAziz Soliman  1 , Marta Iwanaszko  1 , Bin Zheng  1 , Sarah Gold  1 , Benjamin Charles Howard  1 , Madhurima Das  1 , Ram Prosad Chakrabarty  1   2 , Navdeep S Chandel  1   2 , Ali Shilatifard  1
Affiliations

Transcriptional elongation control of hypoxic response

Shimaa Hassan AbdelAziz Soliman et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

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