Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence.

Autor: Rosell-Garcia T; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad Autónoma de Madrid (U.A.M.), Madrid, Spain., Rivas-Muñoz S; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad Autónoma de Madrid (U.A.M.), Madrid, Spain., Kin K; Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Spain., Romero-Albillo V; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad Autónoma de Madrid (U.A.M.), Madrid, Spain., Alcaraz S; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad Autónoma de Madrid (U.A.M.), Madrid, Spain., Fernandez-Tornero C; Centro de Investigaciones Biológicas Margarita Salas, CSIC, Madrid, Spain., Rodriguez-Pascual F; Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad Autónoma de Madrid (U.A.M.), Madrid, Spain. Electronic address: frodriguez@cbm.csic.es.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Gene regulatory mechanisms [Biochim Biophys Acta Gene Regul Mech] 2023 Dec; Vol. 1866 (4), pp. 194963. Date of Electronic Publication: 2023 Jul 25.
DOI: 10.1016/j.bbagrm.2023.194963
Abstrakt: Transcriptional activity of the hypoxia inducible factor (HIF) relies on the formation of a heterodimer composed of an oxygen-regulated α-subunit and a stably expressed β-subunit. Heterodimeric HIF activates expression by binding to RCGTG motifs within promoters of hypoxia-activated genes. Some hypoxia targets also possess an adjacent HIF ancillary sequence (HAS) reported to increase transcription but whose function remains obscure. Here, we investigate the contribution of the HAS element to the hypoxia response and its mechanism of action, using the HAS-containing prolyl 4-hydroxylase subunit α1 (P4HA1) as a gene model in NIH/3T3 mouse embryonic fibroblasts and HEK293 human embryonic kidney cells. Our HIF overexpression experiments demonstrate that the HAS motif is essential for full induction by hypoxia and that the presence of the tandem HAS/HIF, as opposed to HIF-only sequences, provides HIF proteins with the capacity to form complexes of stoichiometry beyond the classical heterodimer, likely tetramers, to cooperatively potentiate hypoxia-induced transcription. We also provide evidence of the crucial role played by the Fα helix of the PAS-B domain of the HIF1β subunit to support the interaction between heterodimers. Functional analysis showed that human genes containing the HAS/HIF motifs are better responders to hypoxia, and their promoters are enriched for specific transcription factor binding sites. Gene ontology enrichment revealed a predominance of HAS/HIF in genes primarily related to tissue formation and development. Our findings add an extra level of regulation of the hypoxia/HIF signaling through multimerization of HIF proteins on regulatory elements containing the HAS/HIF motifs.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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