biostudies-literatureChen YHoward Hughes Medical InstituteNCI NIH HHSNational Institutes of HealthNIH HHSe75064https://www.ebi.ac.uk/biostudies/studies/S-EPMC9681212biostudies-literatureUnknown11Transcription factors (TFs) are classically attributed a modular construction, containing well-structured sequence-specific DNA-binding domains (DBDs) paired with disordered activation domains (ADs) responsible for protein-protein interactions targeting co-factors or the core transcription initiation machinery. However, this simple division of labor model struggles to explain why TFs with identical DNA-binding sequence specificity determined in vitro exhibit distinct binding profiles in vivo. The family of hypoxia-inducible factors (HIFs) offer a stark example: aberrantly expressed in several cancer types, HIF-1α and HIF-2α subunit isoforms recognize the same DNA motif in vitro - the hypoxia response element (HRE) - but only share a subset of their target genes in vivo, while eliciting coneLifeMechanisms governing target search and binding dynamics of hypoxia-inducible factors.PMC9681212S10 OD018174U54 CA231641U54-CA231641-01Tjian RDarzacq XChen YCattoglio CDailey GMZhu QfalseMechanisms governing target search and binding dynamics of hypoxia-inducible factors.Transcription factors (TFs) are classically attributed a modular construction, containing well-structured sequence-specific DNA-binding domains (DBDs) paired with disordered activation domains (ADs) responsible for protein-protein interactions targeting co-factors or the core transcription initiation machinery. However, this simple division of labor model struggles to explain why TFs with identical DNA-binding sequence specificity determined in vitro exhibit distinct binding profiles in vivo. The family of hypoxia-inducible factors (HIFs) offer a stark example: aberrantly expressed in several cancer types, HIF-1α and HIF-2α subunit isoforms recognize the same DNA motif in vitro - the hypoxia response element (HRE) - but only share a subset of their target genes in vivo, while eliciting con2022-01-01T00:00:00Z2022 Nov2026-05-10T06:35:14.048Z2025-02-19T04:20:09.367ZS-EPMC96812123632245610.7554/eLife.75064