REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

Miguel A.S. Cavadas; Marion Mesnieres; Bianca Crifo; Mario C. Manresa; Andrew C. Selfridge; Carsten C. Scholz; Eoin P. Cummins; Alex Cheong; Cormac T. Taylor

doi:10.1038/srep17851

REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

Miguel A.S. Cavadas, Marion Mesnieres, Bianca Crifo, Mario C. Manresa, Andrew C. Selfridge, Carsten C. Scholz, Eoin P. Cummins, Alex Cheong^*, Cormac T. Taylor

^*Corresponding author for this work

Aston Pharmacy School

Research output: Contribution to journal › Article › peer-review

Abstract

The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

Original language	English
Article number	17851
Number of pages	12
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep17851
Publication status	Published - 9 Dec 2015

Bibliographical note

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Supplementary Information: http://www.nature.com/article-assets/npg/srep/2015/151209/srep17851/extref/srep17851-s1.pdf

Access to Document

10.1038/srep17851Licence: CC BY 3.0

HIF-dependent gene expression in prolonged hypoxia
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Final published version, 1.59 MBLicence: CC BY 3.0

Cite this

@article{55581eb123954a7992a34d0259dc87c4,

title = "REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia",

abstract = "The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.",

author = "Cavadas, {Miguel A.S.} and Marion Mesnieres and Bianca Crifo and Manresa, {Mario C.} and Selfridge, {Andrew C.} and Scholz, {Carsten C.} and Cummins, {Eoin P.} and Alex Cheong and Taylor, {Cormac T.}",

note = "This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Supplementary Information: http://www.nature.com/article-assets/npg/srep/2015/151209/srep17851/extref/srep17851-s1.pdf",

year = "2015",

month = dec,

day = "9",

doi = "10.1038/srep17851",

language = "English",

volume = "5",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

AU - Cavadas, Miguel A.S.

AU - Mesnieres, Marion

AU - Crifo, Bianca

AU - Manresa, Mario C.

AU - Selfridge, Andrew C.

AU - Scholz, Carsten C.

AU - Cummins, Eoin P.

AU - Cheong, Alex

AU - Taylor, Cormac T.

N1 - This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Supplementary Information: http://www.nature.com/article-assets/npg/srep/2015/151209/srep17851/extref/srep17851-s1.pdf

PY - 2015/12/9

Y1 - 2015/12/9

N2 - The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

AB - The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

UR - http://www.scopus.com/inward/record.url?scp=84949562886&partnerID=8YFLogxK

U2 - 10.1038/srep17851

DO - 10.1038/srep17851

M3 - Article

AN - SCOPUS:84949562886

SN - 2045-2322

VL - 5

JO - Scientific Reports

JF - Scientific Reports

M1 - 17851

ER -

REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this