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REST is a hypoxia-responsive transcriptional repressor


Abstract

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic a
pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to
hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive
gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent
gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and
repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of
the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST
is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin
immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part
mediated by direct binding to the promoters of target genes. Based on these data, we propose that
REST is a key mediator of gene repression in hypoxia.

Abstract

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic a
pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to
hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive
gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent
gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and
repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of
the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST
is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin
immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part
mediated by direct binding to the promoters of target genes. Based on these data, we propose that
REST is a key mediator of gene repression in hypoxia.

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Contributors:Professor Louis B. Hersh (University of Kentucky, USA) for the kind gift of the msREST-FLAG, Dr Ian Wood (University of Leeds, UK) for the rat SCN2A RE1 sequence
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:24 Aug 2016 15:51
Last Modified:24 Aug 2016 16:00
Publisher:Nature Publishing Group
ISSN:2045-2322
Funders:Science Foundation Ireland under Grant No. 06/CE/B1129
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/srep31355

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Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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