Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network.
Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network.
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DOI：
10.3389/fgene.2013.00188
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发表时间：
2013
影响因子：
3.7
通讯作者：
Rutkowski DT
中科院分区：
文献类型：
--
作者：
Arensdorf AM;Dezwaan McCabe D;Kaufman RJ;Rutkowski DT
未折叠蛋白反应（UPR）通过启动信号级联反应来响应内质网（ER）功能的破坏，最终导致广泛的转录调控。传统上，这种调节包括编码ER伴侣蛋白、ER相关降解因子和参与分泌蛋白折叠和加工的其他因子的基因，并且通过作为UPR激活的结果产生的转录激活因子来进行。然而，多达一半的mRNA的ER应激调节下调，而不是上调，和ER应激和UPR激活mRNA抑制的机制知之甚少。为了开始解决这个问题，我们使用了“自下而上”的方法来研究肝脏中由UPR控制的代谢基因调控网络，因为肝脏中的ER应激导致脂质积聚，而脂肪肝疾病是西方世界最常见的肝病。ER应激期间小鼠肝脏mRNA的qRT-PCR分析显示，转录调节因子C/EBPα、PPARα和PGC-1α的抑制先于脂质蓄积，然后是编码参与脂肪酸氧化和脂蛋白生物合成和转运的关键酶的mRNA的抑制。缺乏ER应激传感器ATF 6 α的小鼠在挑战期间经历持续的ER应激和严重的脂质积累，然后被用作功能基因组学方法的基础，该方法允许基因被分组为不同的表达谱。这种聚类预测，ER应激会抑制代谢转录调节因子HNF 4 α的活性-随后通过Cebpa和Pgc 1a启动子的染色质免疫沉淀证实了这一发现。我们的研究结果建立了一个框架，在ER应激过程中的肝脏基因调控，并建议HNF 4 α占据该框架的顶点。他们还提供了一个独特的资源，为社会进一步探索ER应激过程中的基因表达的时间调控在体内。
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.