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Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network
The unfolded protein response (UPR) responds to disruption of endoplasmic reticulum (ER) function by initiating signaling cascades that ultimately culminate in extensive transcriptional regulation. Classically, this regulation includes genes encoding ER chaperones, ER-associated degradation factors,...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781334/ https://www.ncbi.nlm.nih.gov/pubmed/24069029 http://dx.doi.org/10.3389/fgene.2013.00188 |
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author | Arensdorf, Angela M. DeZwaan McCabe, Diane Kaufman, Randal J. Rutkowski, D. Thomas |
author_facet | Arensdorf, Angela M. DeZwaan McCabe, Diane Kaufman, Randal J. Rutkowski, D. Thomas |
author_sort | Arensdorf, Angela M. |
collection | PubMed |
description | The unfolded protein response (UPR) responds to disruption of endoplasmic reticulum (ER) function by initiating signaling cascades that ultimately culminate in extensive transcriptional regulation. Classically, this regulation includes genes encoding ER chaperones, ER-associated degradation factors, and others involved in secretory protein folding and processing, and is carried out by the transcriptional activators that are produced as a consequence of UPR activation. However, up to half of the mRNAs regulated by ER stress are downregulated rather than upregulated, and the mechanisms linking ER stress and UPR activation to mRNA suppression are poorly understood. To begin to address this issue, we used a “bottom-up” approach to study the metabolic gene regulatory network controlled by the UPR in the liver, because ER stress in the liver leads to lipid accumulation, and fatty liver disease is the most common liver disease in the western world. qRT-PCR profiling of mouse liver mRNAs during ER stress revealed that suppression of the transcriptional regulators C/EBPα, PPARα, and PGC-1α preceded lipid accumulation, and was then followed by suppression of mRNAs encoding key enzymes involved in fatty acid oxidation and lipoprotein biogenesis and transport. Mice lacking the ER stress sensor ATF6α, which experience persistent ER stress and profound lipid accumulation during challenge, were then used as the basis for a functional genomics approach that allowed genes to be grouped into distinct expression profiles. This clustering predicted that ER stress would suppress the activity of the metabolic transcriptional regulator HNF4α—a finding subsequently confirmed by chromatin immunopreciptation at the Cebpa and Pgc1a promoters. Our results establish a framework for hepatic gene regulation during ER stress and suggest that HNF4α occupies the apex of that framework. They also provide a unique resource for the community to further explore the temporal regulation of gene expression during ER stress in vivo. |
format | Online Article Text |
id | pubmed-3781334 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-37813342013-09-25 Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network Arensdorf, Angela M. DeZwaan McCabe, Diane Kaufman, Randal J. Rutkowski, D. Thomas Front Genet Endocrinology The unfolded protein response (UPR) responds to disruption of endoplasmic reticulum (ER) function by initiating signaling cascades that ultimately culminate in extensive transcriptional regulation. Classically, this regulation includes genes encoding ER chaperones, ER-associated degradation factors, and others involved in secretory protein folding and processing, and is carried out by the transcriptional activators that are produced as a consequence of UPR activation. However, up to half of the mRNAs regulated by ER stress are downregulated rather than upregulated, and the mechanisms linking ER stress and UPR activation to mRNA suppression are poorly understood. To begin to address this issue, we used a “bottom-up” approach to study the metabolic gene regulatory network controlled by the UPR in the liver, because ER stress in the liver leads to lipid accumulation, and fatty liver disease is the most common liver disease in the western world. qRT-PCR profiling of mouse liver mRNAs during ER stress revealed that suppression of the transcriptional regulators C/EBPα, PPARα, and PGC-1α preceded lipid accumulation, and was then followed by suppression of mRNAs encoding key enzymes involved in fatty acid oxidation and lipoprotein biogenesis and transport. Mice lacking the ER stress sensor ATF6α, which experience persistent ER stress and profound lipid accumulation during challenge, were then used as the basis for a functional genomics approach that allowed genes to be grouped into distinct expression profiles. This clustering predicted that ER stress would suppress the activity of the metabolic transcriptional regulator HNF4α—a finding subsequently confirmed by chromatin immunopreciptation at the Cebpa and Pgc1a promoters. Our results establish a framework for hepatic gene regulation during ER stress and suggest that HNF4α occupies the apex of that framework. They also provide a unique resource for the community to further explore the temporal regulation of gene expression during ER stress in vivo. Frontiers Media S.A. 2013-09-24 /pmc/articles/PMC3781334/ /pubmed/24069029 http://dx.doi.org/10.3389/fgene.2013.00188 Text en Copyright © 2013 Arensdorf, DeZwaan McCabe, Kaufman and Rutkowski. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Arensdorf, Angela M. DeZwaan McCabe, Diane Kaufman, Randal J. Rutkowski, D. Thomas Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network |
title | Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network |
title_full | Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network |
title_fullStr | Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network |
title_full_unstemmed | Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network |
title_short | Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network |
title_sort | temporal clustering of gene expression links the metabolic transcription factor hnf4α to the er stress-dependent gene regulatory network |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781334/ https://www.ncbi.nlm.nih.gov/pubmed/24069029 http://dx.doi.org/10.3389/fgene.2013.00188 |
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