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.