Hypoxia-responsive interaction between P-TEFb, BHLHE40, and Tim8-Tim13 regulates hypoxic gene transcription

  • Sci Adv. 2026 May 22;12(21):eadz9295. doi: 10.1126/sciadv.adz9295.
Shimaa Hassan AbdelAziz Soliman  1 ,  Simone De Fabritiis  1 ,  Marta Iwanaszko  1 ,  Lawrence Austin Lin  1 ,  Madhurima Das  1 ,  Sarah Gold  1 ,  Grant David Andersen  1 ,  Ram P Chakrabarty  2 ,  Navdeep S Chandel  1  2 ,  Ali Shilatifard  1
Affiliations
  • 1. Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.
PMID: 42160428 DOI: 10.1126/sciadv.adz9295
Abstract

The P-TEFb transcriptional kinase complex regulates the pause release checkpoint step in transcription by RNA polymerase II (RNAPII). We sought to identify hypoxia-specific interactions that could direct P-TEFb activity to hypoxia-responsive genes. Using a biochemical purification approach, we discovered a hypoxia-specific, chromatin-associated interaction between the P-TEFb subunit cyclin T1 (CCNT1), nuclear localized mitochondrial chaperone Tim8-Tim13 complexes, and the hypoxia-inducible, DNA binding transcription factor BHLHE40. This interaction is confirmed across multiple human cell lines. Tim8-Tim13 complex disruption and BHLHE40 silencing both impair the transcriptional response to acute hypoxia. HIF is not involved in the CCNT1/BHLHE40/Tim8-Tim13 interaction, and neither genetic HIF-1β knockout nor pharmacological HIF-2α inhibition (belzutifan) eliminates BHLHE40 expression. Finally, BHLHE40 depletion compromises the proliferation of 786-O clear cell renal carcinoma cells, which constitutively express HIF-2α and hypoxia-responsive genes. Together, these findings reveal a partially HIF-independent regulatory axis, in which Tim8-Tim13 complexes and BHLHE40 modulate P-TEFb activity in the transcriptional response to hypoxia.

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