Xiang Gao

Qingdao University of Science and Technology

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Zhaoyu Lin

Sun Yat-sen Memorial Hospital

Qing Jiang

Nanjing Drum Tower Hospital

Chaojun Li

Nanjing Medical University

Peiliang Shi

Chengdu Organic Chemicals (China)

Zan Huang

Nanjing Agricultural University

Huangxian Ju

Nanjing University

Dayuan Zou

Model Animal Research Center

Anying Song

City of Hope

Yi Cao

Collaborative Innovation Center of Advanced Microstructures

Huajian Teng

Nanjing Drum Tower Hospital

Cooperative Institutions

Nanjing University

146

Chinese Academy of Sciences

Model Animal Research Center

Nanjing Drum Tower Hospital

Nanjing Medical University

Helmholtz Zentrum München

German Center for Neurodegenerative Diseases

Technical University of Munich

Munich Cluster for Systems Neurology

University of Chinese Academy of Sciences

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Generation of Genetically Modified Mice by Oocyte Injection of Androgenetic Haploid Embryonic Stem Cells

Cell (2012)

Hui Yang Linyu Shi Bang-An Wang Dan Liang Cuiqing Zhong

Parthenogenesis

Gamete

10.1016/j.cell.2012.04.002

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Citations (182)

Coupling of mitochondrial function and skeletal muscle fiber type by a miR‐499/Fnip1/ AMPK circuit

EMBO Molecular Medicine (2016)

Jing Liu Xijun Liang Danxia Zhou Ling‐Ping Lai Liwei Xiao

Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative-type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499, parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1α-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, an AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1α. Inhibition of Fnip1 reactivated AMPK/PGC-1α signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function.

AMP-Activated Protein Kinase

10.15252/emmm.201606372

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Citations (96)

Fine-Tuning of Shh/Gli Signaling Gradient by Non-proteolytic Ubiquitination during Neural Patterning

Cell Reports (2019)

Pengcheng Ma Ning‐Ning Song Yongxin Li Qiong Zhang Lei Zhang

Sonic Hedgehog (Shh) signaling plays crucial roles in patterning the ventral neural tube, which is transformed into opposing gradients of repressor and activator forms of Glis. Here, we show that the fine-tuning of the shape of the Gli gradients through non-proteolytic ubiquitination-mediated nuclear exportation plays an important role in the control of local neural cell fate. Loss of RNF220, a ventral neural-specific ubiquitin E3 ligase, leads to ventral expansion of the intermediate V0 and dorsal expansion of the ventral V3 neurons, while reducing the V1, V2, and motor neurons between them. We show that RNF220 interacts with all Glis, either in their activator or repressor forms; induces their K63-linked ubiquitination; and promotes their nuclear export, likely by unmasking a nuclear export signal in the zinc finger domain. We propose that RNF220 works to refine the Gli gradients during neural patterning by limiting the effective Gli levels in the nucleus.

Nuclear export signal

Neural Development

GLI3

10.1016/j.celrep.2019.06.017

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Citations (33)

Loss of conserved Gsdma3 self-regulation causes autophagy and cell death

Biochemical Journal (2015)

Peiliang Shi An Tang Xian Li Siyuan Hou Dayuan Zou

Gasdermin A3 (Gsdma3) was originally identified in association with hair-loss phenotype in mouse mutants. Our previous study found that AE mutant mice, with a Y344H substitution at the C-terminal domain of Gsdma3, display inflammation-dependent alopecia and excoriation [Zhou et al. (2012) Am. J. Pathol. 180, 763–774]. Interestingly, we found that the newly-generated null mutant of Gsdma3 mice did not display the skin dysmorphology, indicating that Gsdma3 is not essential for differentiation of epidermal cells and maintenance of the hair cycle in normal physiological conditions. Consistently, human embryonic kidney (HEK)293 and HaCaT cells transfected with wild-type (WT) Gsdma3 did not show abnormal morphology. However, Gsdma3 Y344H mutation induced autophagy. Gsdma3 N-terminal domain, but not the C-terminal domain, also displayed the similar pro-autophagic activity. The Gsdma3 Y344H mutant protein and N-terminal domain-induced autophagy was associated with mitochondria and ROS generation. Co-expression of C-terminal domain reversed the cell autophagy induced by N-terminal domain. Moreover, C-terminal domain could be co-precipitated with N-terminal domain. These data indicated that the potential pro-autophagic activity of WT Gsdma3 protein is suppressed through an intramolecular inhibition mechanism. Studies on other members of the GSDM family suggested this mechanism is conserved in several sub-families.

HaCaT

HEK 293 cells

Wild type

10.1042/bj20150204

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Citations (103)

Ginseng Berry Extract Promotes Maturation of Mouse Dendritic Cells

PLoS ONE (2015)

Wei Zhang Si-Young Cho Xiang Gao Kyung‐Jin Min Qing Yu

Ginseng extract has been shown to possess certain anti-virus, anti-tumor and immune-activating effects. However, the immunostimulatory effect of ginseng berry extract (GB) has been less well characterized. In this study, we investigated the effect of GB on the activation of mouse dendritic cells (DCs) in vitro and in vivo. GB treatment induced up-regulation of co-stimulatory molecules in bone marrow-derived DCs (BMDCs). Interestingly, GB induced a higher degree of co-stimulatory molecule up-regulation than ginseng root extract (GR) at the same concentrations. Moreover, in vivo administration of GB promoted up-regulation of CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-α in spleen DCs. GB also promoted the generation of Th1 and Tc1 cells. Furthermore, Toll like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) signaling pathway were essential for DC activation induced by GB. In addition, GB strongly prompted the proliferation of ovalbumin (OVA)-specific CD4 and CD8 T cells. Finally, GB induced DC activation in tumor-bearing mice and the combination of OVA and GB treatment inhibited B16-OVA tumor cell growth in C57BL/6 mice. These results demonstrate that GB is a novel tumor therapeutic vaccine adjuvant by promoting DC and T cell activation.

CD86

Splenocyte

10.1371/journal.pone.0130926

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Citations (32)

CD4+ T cells memorize obesity and promote weight regain

Cellular and Molecular Immunology (2017)

Jianghuan Zou Beibei Lai Mingzhu Zheng Qin Chen Shujun Jiang

Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown. In this study, we report that immune cells, especially CD4+ T cells, mediate the 'memory' of previous obese status. In a weight gain-loss-regain model, we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain. This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice. Surprisingly, such obesity memory was abrogated by dexamethasone treatment, whereas immunodeficient Rag1-/- and H2A-/- mice failed to establish such memory. Rag1-/- mice repossessed the obesity memory when immune cells or CD4+ T cells isolated from previously obese mice were transferred. Furthermore, depletion of CD4+ T cells led to obesity memory ablation. Taken together, we conclude that CD4+ T cells mediate obesity memory and promote weight regain.

Memorization

10.1038/cmi.2017.36

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Citations (53)

FAK Phosphorylation by ERK Primes Ras-Induced Tyrosine Dephosphorylation of FAK Mediated by PIN1 and PTP-PEST

Molecular Cell (2009)

Yanhua Zheng Yan Xia David H. Hawke Maxime Hallé Michel L. Tremblay

Dephosphorylation

PAK1

10.1016/j.molcel.2009.06.013

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Citations (158)

Depletion of <italic>PHF14</italic>, a novel histone-binding protein gene, causes neonatal lethality in mice due to respiratory failure

Acta Biochimica et Biophysica Sinica (2013)

Qin Huang Lin Zhang Yiguo Wang Chenyi Zhang Shuhua Zhou

The plant homeodomain (PHD) finger is identified in many chromatin-binding proteins, and functions as a 'reader' that recognizes specific epigenetic marks on histone tails, bridging transcription factors and their associated complexes to chromatin, and regulating gene expression. PHD finger-containing proteins perform many biological functions and are involved in many human diseases including cancer. PHF14 is predicted to code for a protein with multiple PHD fingers. However, its function is unidentified. The aim of this study is to characterize PHF14 and investigate its biological significance by employing multiple approaches including mouse gene-targeting knockout, and molecular cloning and characterization. Three transcripts of PHF14 in human cell lines were identified by reverse transcriptase polymerase chain reaction. Two isoforms of PHF14 (PHF14α and PHF14β) were cloned in this study. It was found that PHF14 was ubiquitously expressed in mouse tissues and human cell lines. PHF14α, the major isoform of PHF14, was localized in the nucleus and also bound to chromatin during cell division. Interestingly, co-immunoprecipitation results suggested that PHF14α bound to histones via its PHD fingers. Strikingly, gene-targeting knockout of PHF14 in mice resulted in a neonatal lethality due to respiratory failure. Pathological analysis revealed severe disorders of tissue and cell structures in multiple organs, particularly in the lungs. These results indicated that PHF14 might be an epigenetic regulator and play an important role in the development of multiple organs in mouse.

Chromatin immunoprecipitation

Gene knockout

Knockout mouse

Gene knockin

10.1093/abbs/gmt055

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Citations (24)

Bi-directional regulation of cartilage metabolism by inhibiting BET proteins—analysis of the effect of I-BET151 on human chondrocytes and murine joints

Journal of Orthopaedic Surgery and Research (2018)

Jin Dai Sheng Zhou Qiting Ge Jinzhong Qin Dongyang Chen

Proinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. And a BET protein inhibitor, I-BET151, has been shown to exert an anti-inflammatory effect by repressing the BET protein-mediated expression of inflammatory genes. Our objective is to investigate the effect of I-BET151 on a surgical mouse model of osteoarthritis (OA) and human chondrocytes. We first treated a surgical mouse model of OA with I-BET151 once per day and evaluated the knee joints at 6 and 8 weeks after treatment. We then pretreated the human chondrocytes with I-BET151 prior to treatment with IL-1β or TNF-α and checked the expression and activity of the matrix-degrading enzyme genes. We also checked the expression of ACAN, COL2A1, and SOX9. We demonstrated that I-BET151 could prevent articular cartilage damage in the surgical mouse model of OA at an earlier time after treatment, but not at a later time after treatment. I-BET151 could robustly suppress the IL-1β- and TNF-α-induced expression and activity of several matrix-degrading enzymes in human chondrocytes. I-BET151 could also suppress the expression of ACAN, COL2A1, and SOX9. Our findings suggested that inhibiting BET proteins could exert a repression effect on both of chondrocyte anabolism and catabolism, and the effect of BET protein inhibitor on surgical mouse model of OA needs further evaluation.

Proinflammatory cytokine

Catabolism

Chondrogenesis

Matrix Metalloproteinase 3

10.1186/s13018-018-0797-y

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Citations (10)

Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development

The Journal of Pathology (2012)

Qin Zhang Xue‐Yan He Lai Chen Chenxi Zhang Xiang Gao

Congenital heart defects (CHDs) are the most prevalent human birth defects. More than 85% of CHDs are thought to result from a combination of genetic susceptibilities and environmental stress. However, the stress-related signalling pathways involved remain largely unknown. The p53 transcription factor is a key tumour suppressor and a central regulator of the cellular stress responses. p53 activities are tightly regulated by its inhibitors Mdm2 and Mdm4 at the post-translational level. Here we used the Cre-loxP system to delete Mdm2 (Tie2Cre;Mdm2(FM/FM) ) or one copy of both Mdm2 and Mdm4 (Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) ) in endothelial/endocardial cells and their derivatives in mice to examine the regulation of the p53/Mdm2-Mdm4 pathway during vascular and cardiovascular development. The Tie2Cre;Mdm2(FM/FM) mice died before embryonic day 10.5 (E10.5) and displayed severe vascular defects. On the other hand, the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) mice displayed atrial and ventricular septal defects (ASD, VSD) of the heart, leading to severe heart dysfunction and postnatal death. During cardiac endocardial cushion morphogenesis, p53 activation was associated with defects in both the epithelial-mesenchymal transition (EMT) of the endocardial cells and the post-EMT proliferation of the mesenchymal cells, and the valvuloseptal phenotypes of the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) mice were fully rescued by deletion of one copy of p53. Strikingly, maternal exposure to low-dose X-rays in C57BL/6 mice mimicked the congenital heart malformations seen in the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) model, which was also dependent on p53 status, establishing a link between maternal exposures and CHD susceptibility through the p53 pathway. These data revealed a new regulatory mechanism in cardiac endocardial cushion morphogenesis and suggested a possible cause of CHDs due to environmental stress.

Atrioventricular cushions

Heart development

Cushion

Endocardium

10.1002/path.4077

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Citations (28)