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

Rosell-Garcia, Tamara; Rivas-Muñoz, Sergio; Kin, Koryu; Romero-Albillo, Verónica; Alcaraz, Silvia; Fernandez-Tornero, Carlos; Rodriguez-Pascual, Fernando; Ministerio de Ciencia, Innovación y Universidades (España)

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

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Main Authors:	Rosell-Garcia, Tamara, Rivas-Muñoz, Sergio, Kin, Koryu, Romero-Albillo, Verónica, Alcaraz, Silvia, Fernandez-Tornero, Carlos, Rodriguez-Pascual, Fernando
Other Authors:	Ministerio de Ciencia, Innovación y Universidades (España)
Format:	artículo biblioteca
Published:	Elsevier 2023-12
Subjects:	Hypoxia inducible factor, Hypoxia response, Cooperation, HIF ancillary sequence, HIF binding site,
Online Access:	http://hdl.handle.net/10261/348392
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id	dig-ibe-es-10261-348392
record_format	koha
spelling	dig-ibe-es-10261-3483922024-02-26T13:50:13Z Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence Rosell-Garcia, Tamara Rivas-Muñoz, Sergio Kin, Koryu Romero-Albillo, Verónica Alcaraz, Silvia Fernandez-Tornero, Carlos Rodriguez-Pascual, Fernando Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Ministerio de Ciencia e Innovación (España) La Caixa Hypoxia inducible factor Hypoxia response Cooperation HIF ancillary sequence HIF binding site © 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/). 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. This work was supported by a grant from Spanish Ministerio de Ciencia e Innovacion (Proyecto I+D+i “Retos Investigacion” RTI2018- 095631-B-I00 and PID2022-136703OB-I00 to F.R.P.). K.K. was supported by la Caixa postdoctoral junior Leader fellowship (LCF/BQ/PI20/11760009). 2024-02-26T13:50:13Z 2024-02-26T13:50:13Z 2023-12 2024-02-26T13:50:13Z artículo doi: 10.1016/j.bbagrm.2023.194963 e-issn: 1876-4320 issn: 1874-9399 Biochimica et Biophysica Acta - Gene Regulatory Mechanisms 1866(4): 194963 (2023) http://hdl.handle.net/10261/348392 #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095631-B-I00/ES/ACTIVACION PROTEOLITICA DE LISIL OXIDASAS. APLICACIONES BIOTECNOLOGICAS Y CONTRIBUCION AL REMODELADO DE LA MATRIZ EXTRACELULAR EN EL DESARROLLO DE ENFERMEDADES HUMANAS/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136703OB-I00/ES/IMPACTO DE LA MATRIZ EXTRACELULAR SOBRE LA BIOLOGIA CELULAR Y LA REPROGRAMACION METABOLICA DE LA FIBROSIS ORGANICA/ Publisher's version http://dx.doi.org/10.1016/j.bbagrm.2023.194963 Sí open Elsevier
institution	IBE ES
collection	DSpace
country	España
countrycode	ES
component	Bibliográfico
access	En linea
databasecode	dig-ibe-es
tag	biblioteca
region	Europa del Sur
libraryname	Biblioteca del IBE España
topic	Hypoxia inducible factor Hypoxia response Cooperation HIF ancillary sequence HIF binding site Hypoxia inducible factor Hypoxia response Cooperation HIF ancillary sequence HIF binding site
spellingShingle	Hypoxia inducible factor Hypoxia response Cooperation HIF ancillary sequence HIF binding site Hypoxia inducible factor Hypoxia response Cooperation HIF ancillary sequence HIF binding site Rosell-Garcia, Tamara Rivas-Muñoz, Sergio Kin, Koryu Romero-Albillo, Verónica Alcaraz, Silvia Fernandez-Tornero, Carlos Rodriguez-Pascual, Fernando Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence
description	© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
author2	Ministerio de Ciencia, Innovación y Universidades (España)
author_facet	Ministerio de Ciencia, Innovación y Universidades (España) Rosell-Garcia, Tamara Rivas-Muñoz, Sergio Kin, Koryu Romero-Albillo, Verónica Alcaraz, Silvia Fernandez-Tornero, Carlos Rodriguez-Pascual, Fernando
format	artículo
topic_facet	Hypoxia inducible factor Hypoxia response Cooperation HIF ancillary sequence HIF binding site
author	Rosell-Garcia, Tamara Rivas-Muñoz, Sergio Kin, Koryu Romero-Albillo, Verónica Alcaraz, Silvia Fernandez-Tornero, Carlos Rodriguez-Pascual, Fernando
author_sort	Rosell-Garcia, Tamara
title	Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence
title_short	Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence
title_full	Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence
title_fullStr	Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence
title_full_unstemmed	Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence
title_sort	multimerization of hif enhances transcription of target genes containing the hypoxia ancillary sequence
publisher	Elsevier
publishDate	2023-12
url	http://hdl.handle.net/10261/348392
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Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence

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