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| Status |
Public on Jun 03, 2019 |
| Title |
A genome-wide approach to delineate novel XBP-1 targets involved in liver metabolism |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
This experiment was conducted to identify novel XBP-1 targets involved in liver metabolism. The following abstract from the submitted manuscript describes the major findings of this work.
The IRE1a-XBP1s axis regulates the COPII-mediated secretory program in response to nutrient availability. Lin Liu, Jie Cai, Xijun Liang, Qian Zhou, Huimin Wang, Chenyun Ding, Yuangang Zhu, Liwei Xiao, Tingting Fu, Zhisheng Xu, Jing Liu, Yujing Yin, Lei Fang, Bin Xue, Yan Wang, Aibin He, Yong Liu, Xiao-Wei Chen, and Zhenji Gan
The cytoplasmic coat protein complex-II (COPII) is an evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII-mediated secretion parallel the activation of XBP1s, the critical transcription factor in handling cellular ER stress, in both live cells and mouse liver upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent secretion, mediating the nutrient stimulatory effects. ChIP-seq and RNA-seq analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII secretion-related genes, thereby driving COPII-directed secretory process. Liver-specific disruption of the IRE1a-XBP1s signaling branch results in diminished COPII-mediated secretion. Reactivation of XBP1s in mice lacking hepatic IRE1a restores COPII-mediated lipoprotein secretion, and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid secretion: the IRE1a-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII secretory program.
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| Overall design |
Using genome-wide approach, ChIPseq, to delineate novel XBP-1 targets involved in liver metabolism
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| Contributor(s) |
Zhou Q, Liang X, Liu L, Gan Z |
| Citation(s) |
31123148 |
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| Submission date |
Jul 11, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Zhenji Gan |
| E-mail(s) |
ganzj@nju.edu.cn
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| Organization name |
Nanjing University
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| Department |
Model Animal Research Center of Nanjing University
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| Street address |
12 Xuefu Road
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| City |
Nanjing |
| ZIP/Postal code |
210061 |
| Country |
China |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA393859 |
| SRA |
SRP111551 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE101202_RAW.tar |
1.7 Gb |
(http)(custom) |
TAR (of BEDGRAPH, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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