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Time course XBP1s ChIP-Seq in Xbp1 flx/flx (WT, wild-type) mice and AlbCre;Xbp1 flx/flx (XBP1 LKO, liver-specific knockout) mice

ABSTRACT: We reported the hepatic XBP1s cistrome (starting at CT0 and proceeding every four hours for three complete 12-hour cycles) in the liver of wild-type mice and XBP1 liver-specific knockout mice; we also chose liver samples at CT0 and CT8 (four hours before the dusk 12-hour rhythmic peak) for comprehensive XBP1s ChIP-Seq to interrogate the genomic binding profiles of hepatic XBP1s in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE150889 | GEO | 2020/05/24

REPOSITORIES: GEO

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Project description:This experiment was conducted to identify mRNA transcripts alteration in liver of Ern1 liver specific knockout mice. 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.

Dataset Information

Time course XBP1s ChIP-Seq in Xbp1 flx/flx (WT, wild-type) mice and AlbCre;Xbp1 flx/flx (XBP1 LKO, liver-specific knockout) mice

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