ArticleScience advances2026
Hypoxia-responsive interaction between P-TEFb, BHLHE40, and Tim8-Tim13 regulates hypoxic gene transcription.
Shimaa Hassan AbdelAziz Soliman, Simone De Fabritiis, Marta Iwanaszko, Lawrence Austin Lin, Madhurima Das, Sarah Gold, Grant David Andersen, Ram P Chakrabarty, Navdeep S Chandel, Ali Shilatifard
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In one paragraphArticle in Science advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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What it found
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5 · Who and what moneyAuthors and funding
10 authors.
Shimaa Hassan AbdelAziz SolimanSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0001-6517-9847 Simone De FabritiisSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0001-6404-6962 Marta IwanaszkoSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0001-6909-5931 Lawrence Austin LinSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0009-0008-6077-7600 Madhurima DasSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Sarah GoldSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0001-7390-4121 Grant David AndersenSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0009-0006-5517-6240 Ram P ChakrabartyDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0002-5425-6306 Navdeep S ChandelSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0001-7208-3886 Ali ShilatifardSimpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID 0000-0002-7490-2854 Funding
Computational Approaches for Studying Transcription Elongation Control in CancerR50CA265372 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Marta Iwanaszko · 2022 to 2026
$722kNCI NIH HHS R50 CA265372
6 · The paper itselfAbstract
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.
Indexed as
Basic Helix-Loop-Helix ProteinsGene Expression RegulationHypoxiaMembrane ProteinsPositive Transcriptional Elongation Factor BTranscription, GeneticCell HypoxiaCell Line, TumorEndothelial PAS Domain-Containing Protein 1HumansMitochondrial Precursor Protein Import Complex ProteinsProtein BindingBasic Helix-Loop-Helix ProteinsEndothelial PAS Domain-Containing Protein 1Membrane ProteinsMitochondrial Precursor Protein Import Complex ProteinsPositive Transcriptional Elongation Factor B
Identifiers
PMID42160428
PMCPMC13189126
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