Journal of Genetics and Genomics

The E3 Ubiquitin Ligase gp78 Protects against ER Stress in Zebrafish Liver

Zhiliang Chen, Petek Ballar, Yu Fu, Jia Luo, Shaojun Du, Shengyun Fang

2014, 41(7): 357-368. doi: 10.1016/j.jgg.2014.05.005

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Abstract:
Enhanced endoplasmic reticulum (ER)-associated protein degradation (ERAD) activity by the unfolded protein response (UPR) represents one of the mechanisms for restoring ER homeostasis. In vitro evidence indicates that the mammalian gp78 protein is an E3 ubiquitin ligase that facilitates ERAD by polyubiquitinating and targeting proteins for proteasomal degradation under both physiologic and stress conditions. However, the in vivo function of gp78 in maintaining ER protein homeostasis remains untested. Here we show that like its mammalian counterpart, the zebrafish gp78 is also an E3 ubiquitin ligase as revealed by in vitro ubiquitination assays. Expression analysis uncovered that gp78 is highly expressed in several organs, including liver and brain, of both larval and adult fish. Treatment of larvae or adult fish with tunicamycin induces ER stress and upregulates the expression of several key components of the gp78 ERAD complex in the liver. Moreover, liver-specific overexpression of the dominant-negative form of gp78 (gp78-R2M) renders liver more sensitive to tunicamycin-induced ER stress and enhances the expression of sterol response element binding protein (Srebp)-target genes, which was largely suppressed in fish overexpressing wild-type gp78. Together, these data indicate that gp78 plays a critical role in protecting against ER stress in liver.

Drosophila heparan sulfate 3-O sulfotransferase B Null Mutant Is Viable and Exhibits No Defects in Notch Signaling

Yueqin Guo, Ying Feng, Zhouhua Li, Xinhua Lin

2014, 41(7): 369-378. doi: 10.1016/j.jgg.2014.04.006

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Abstract:
Heparan sulfate proteoglycans (HSPGs) are critically involved in a variety of biological events. The functions of HSPGs are determined by the nature of the core proteins and modifications of heparan sulfate (HS) glycosaminoglycan (GAG) chains. The distinct O-sulfotransferases are important for nonrandom modifications at specific positions. Two HS 3-O sulfotransferase (Hs3st) genes, Hs3st-A and Hs3st-B, were identified in Drosophila. Previous experiments using RNA interference (RNAi) suggested that Hs3st-B was required for Notch signaling. Here, we generated a null mutant of Hs3st-B via ends-out gene targeting and examined its role(s) in development. We found that homozygous Hs3st-B mutants have no neurogenic defects or alterations in the expression of Notch signaling target gene. Thus, our results strongly argue against an essential role for Hs3st-B in Notch signaling. Moreover, we have generated two independent Hs3st-A RNAi lines which worked to deplete Hs3st-A. Importantly, Hs3st-A RNAi combined with Hs3st-B mutant flies did not alter the expression of Notch signaling components, arguing that both Hs3st-A and Hs3st-B were not essential for Notch signaling. The establishment of Hs3st-B mutant and effective Hs3st-A RNAi lines provides essential tools for further studies of the physiological roles of Hs3st-A and Hs3st-B in development and homeostasis.

Transcriptomic Response to Yersinia pestis: RIG-I Like Receptor Signaling Response Is Detrimental to the Host against Plague

Zongmin Du, Huiying Yang, Yafang Tan, Guang Tian, Qingwen Zhang, Yujun Cui, Yanfeng Yan, Xiaohong Wu, Zuyun Chen, Shiyang Cao, Yujing Bi, Yanping Han, Xiaoyi Wang, Yajun Song, Ruifu Yang

2014, 41(7): 379-396. doi: 10.1016/j.jgg.2014.05.006

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Abstract:
Bacterial pathogens have evolved various mechanisms to modulate host immune responses for successful infection. In this study, RNA-sequencing technology was used to analyze the responses of human monocytes THP1 to Yersinia pestis infection. Over 6000 genes were differentially expressed over the 12 h infection. Kinetic responses of pathogen recognition receptor signaling pathways, apoptosis, antigen processing, and presentation pathway and coagulation system were analyzed in detail. Among them, RIG-I-like receptor (RLR) signaling pathway, which was established for antiviral defense, was significantly affected. Mice lacking MAVS, the adaptor of the RLR signaling pathway, were less sensitive to infection and exhibited lower IFN-β production, higher Th1-type cytokines IFN-γ and IL-12 production, and lower Th2-type cytokines IL-4 and IL-13 production in the serum compared with wild-type mice. Moreover, infection of pathogenic bacteria other than Y. pestis also altered the expression of the RLR pathway, suggesting that the response of RLR pathway to bacterial infection is a universal mechanism.

A Matrilineal Genetic Legacy from the Last Glacial Maximum Confers Susceptibility to Schizophrenia in Han Chinese

Wen Zhang, Jinsong Tang, A-Mei Zhang, Min-Sheng Peng, Hai-Bing Xie, Liwen Tan, Lin Xu, Ya-Ping Zhang, Xiaogang Chen, Yong-Gang Yao

2014, 41(7): 397-407. doi: 10.1016/j.jgg.2014.05.004

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Abstract:
Mitochondrial dysfunction has been widely reported in schizophrenia patients. To dissect the matrilineal structure of Han Chinese with or without schizophrenia and to decipher the maternal influence and evolutionary history of schizophrenia, a total of 1212 schizophrenia patients and 1005 matched healthy controls, all of Han Chinese origin, were recruited in Hunan Province, China. We classified haplogroup for each individual based on mitochondrial DNA (mtDNA) sequence variations and compared the haplogroup distribution pattern between cases and controls. Haplogroup B5a presented a higher frequency in cases than in controls (P = 0.02, OR = 1.67, 95% CI = [1.09, 2.56]), and this result could be confirmed by permutation analysis. Age estimation of haplogroup B5a in cases revealed a much younger age than that of controls, which was coincident with the Northern Hemisphere deglaciation at the end of the Last Glacial Maximum. Analysis of complete mtDNA in five patients belonging to haplogroup B5a showed that this background effect might be caused by haplogroup-defining variants m.8584G>A and m.10398A>G. Our results showed that matrilineal risk factor for schizophrenia had an ancient origin and might acquire a predisposing effect on schizophrenia due to the environment change and/or orchestration with other nuclear genetic factors appeared recently in human evolutionary history.

RNA Guided Genome Editing in Mouse Germ-Line Stem Cells

Xuepeng Wang, Yan Yuan, Quan Zhou, Haifeng Wan, Mei Wang, Qi Zhou, Xiao-Yang Zhao, Jiahao Sha

2014, 41(7): 409-411. doi: 10.1016/j.jgg.2014.06.001

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Abstract:

Genome of Staphylococcus xylosus and Comparison with S. aureus and S. epidermidis

Xiaojuan Tan, Lin Liu, Shili Liu, Dongting Yang, Yikun Liu, Shuang Yang, Aiqun Jia, Nan Qin

2014, 41(7): 413-416. doi: 10.1016/j.jgg.2014.03.007

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Abstract:

2014 Vol. 41, No. 7