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class="affiliations-container fake-truncate js-profile-affiliations"><div><a class="u-tcGrayDarker" href="https://kernkracht.academia.edu/">Kuleuven</a>, <a class="u-tcGrayDarker" href="https://kernkracht.academia.edu/Departments/Skeletal_Biology_and_engineering/Documents">Skeletal Biology and engineering</a>, <span class="u-tcGrayDarker">Graduate Student</span></div></div></div></div><div class="sidebar-cta-container"><button class="ds2-5-button hidden profile-cta-button grow js-profile-follow-button" data-broccoli-component="user-info.follow-button" data-click-track="profile-user-info-follow-button" data-follow-user-fname="Marion" data-follow-user-id="47811246" data-follow-user-source="profile_button" data-has-google="false"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">add</span>Follow</button><button class="ds2-5-button hidden profile-cta-button grow js-profile-unfollow-button" data-broccoli-component="user-info.unfollow-button" 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class="ri-section"><div class="ri-section-header"><span>Interests</span></div><div class="ri-tags-container"><a data-click-track="profile-user-info-expand-research-interests" data-has-card-for-ri-list="47811246" href="https://www.academia.edu/Documents/in/Hypoxia"><div id="js-react-on-rails-context" style="display:none" data-rails-context="{"inMailer":false,"i18nLocale":"en","i18nDefaultLocale":"en","href":"https://kernkracht.academia.edu/MarionMesnieres","location":"/MarionMesnieres","scheme":"https","host":"kernkracht.academia.edu","port":null,"pathname":"/MarionMesnieres","search":null,"httpAcceptLanguage":null,"serverSide":false}"></div> <div class="js-react-on-rails-component" style="display:none" data-component-name="Pill" data-props="{"color":"gray","children":["Hypoxia"]}" data-trace="false" data-dom-id="Pill-react-component-998c2316-d0eb-436a-b40c-bf1e65556423"></div> <div id="Pill-react-component-998c2316-d0eb-436a-b40c-bf1e65556423"></div> </a><a 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</a></div></div><div class="external-links-container"><ul class="profile-links new-profile js-UserInfo-social"><li class="profile-profiles js-social-profiles-container"><i class="fa fa-spin fa-spinner"></i></li></ul></div></div></div><div class="right-panel-container"><div class="user-content-wrapper"><div class="uploads-container" id="social-redesign-work-container"><div class="upload-header"><h2 class="ds2-5-heading-sans-serif-xs">Uploads</h2></div><div class="documents-container backbone-social-profile-documents" style="width: 100%;"><div class="u-taCenter"></div><div class="profile--tab_content_container js-tab-pane tab-pane active" id="all"><div class="profile--tab_heading_container js-section-heading" data-section="Papers" id="Papers"><h3 class="profile--tab_heading_container">Papers by Marion Mesnieres</h3></div><div class="js-work-strip profile--work_container" data-work-id="31739493"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor"><img alt="Research paper thumbnail of REST is a hypoxia-responsive transcriptional repressor" class="work-thumbnail" src="https://attachments.academia-assets.com/52048513/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor">REST is a hypoxia-responsive transcriptional repressor</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://ucd.academia.edu/CiaraKeogh">Ciara Keogh</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/ZsoltFabian1">Zsolt Fabian</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AnitaWdowicz">Anita Wdowicz</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/EoinCummins">Eoin Cummins</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AlexCheong1">Alex Cheong</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pat...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and 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.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5402e0b2c062eef5d20dbcda96beb948" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52048513,"asset_id":31739493,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52048513/download_file?st=MTczMjk5ODQzNyw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31739493"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31739493"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31739493; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31739493]").text(description); $(".js-view-count[data-work-id=31739493]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31739493; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31739493']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31739493, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5402e0b2c062eef5d20dbcda96beb948" } } $('.js-work-strip[data-work-id=31739493]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31739493,"title":"REST is a hypoxia-responsive transcriptional repressor","translated_title":"","metadata":{"abstract":"Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744858"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN"><img alt="Research paper thumbnail of REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN" class="work-thumbnail" src="https://attachments.academia-assets.com/45073645/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN">REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/MManresa">M. Manresa</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which p...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">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. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 .</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="acb327469b8e3627688d02df2b6a2522" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073645,"asset_id":24744858,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073645/download_file?st=MTczMjk5ODQzNyw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744858"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744858"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744858; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744858]").text(description); $(".js-view-count[data-work-id=24744858]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744858; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744858']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744858, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "acb327469b8e3627688d02df2b6a2522" } } $('.js-work-strip[data-work-id=24744858]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744858,"title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN","translated_title":"","metadata":{"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. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 ."},"translated_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. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> </div><div class="profile--tab_content_container js-tab-pane tab-pane" data-section-id="5116394" id="papers"><div class="js-work-strip profile--work_container" data-work-id="31739493"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor"><img alt="Research paper thumbnail of REST is a hypoxia-responsive transcriptional repressor" class="work-thumbnail" src="https://attachments.academia-assets.com/52048513/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor">REST is a hypoxia-responsive transcriptional repressor</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://ucd.academia.edu/CiaraKeogh">Ciara Keogh</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/ZsoltFabian1">Zsolt Fabian</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AnitaWdowicz">Anita Wdowicz</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/EoinCummins">Eoin Cummins</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AlexCheong1">Alex Cheong</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pat...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and 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.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5402e0b2c062eef5d20dbcda96beb948" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52048513,"asset_id":31739493,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52048513/download_file?st=MTczMjk5ODQzNyw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31739493"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31739493"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31739493; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31739493]").text(description); $(".js-view-count[data-work-id=31739493]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31739493; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31739493']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31739493, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5402e0b2c062eef5d20dbcda96beb948" } } $('.js-work-strip[data-work-id=31739493]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31739493,"title":"REST is a hypoxia-responsive transcriptional repressor","translated_title":"","metadata":{"abstract":"Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744858"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN"><img alt="Research paper thumbnail of REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN" class="work-thumbnail" src="https://attachments.academia-assets.com/45073645/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN">REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/MManresa">M. Manresa</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which p...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">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. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 .</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="acb327469b8e3627688d02df2b6a2522" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073645,"asset_id":24744858,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073645/download_file?st=MTczMjk5ODQzNyw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744858"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744858"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744858; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744858]").text(description); $(".js-view-count[data-work-id=24744858]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744858; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744858']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744858, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "acb327469b8e3627688d02df2b6a2522" } } $('.js-work-strip[data-work-id=24744858]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744858,"title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN","translated_title":"","metadata":{"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. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 ."},"translated_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. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. 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