Latest Articles

Unc-51-like kinase (ULK) complex-independent autophagy induced by hypoxia
Yan Feng, Helen H. Kang, Pui-Mun Wong, Minghui Gao, Ping Wang, Xuejun Jiang
TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy
Guoxing Zheng, Changying Jiang, Yulin Li, Dandan Yang, Youcai Ma, Bing Zhang, Xuan Li, Pei Zhang, Xiaoyu Hu, Xueqiang Zhao, Jie Du, Xin Lin
 doi: 10.1007/s13238-018-0563-2
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiac muscle disease that accounts for approximately 30% sudden cardiac death in young adults. The Ser358Leu mutation of transmembrane protein 43 (TMEM43) was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype, ARVD5. Here, we generated TMEM43 S358L mouse to explore the underlying mechanism. This mouse strain showed the classic pathologies of ARVD patients, including structural abnormalities and cardiac fibrofatty. TMEM43 S358L mutation led to hyper-activated nuclear factor κB (NF-κB) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGFβ1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development.
In vitro transcribed sgRNA causes cell death by inducing interferon release
Wei Mu, Na Tang, Chen Cheng, Wen Sun, Xiaofei Wei, Haoyi Wang
RETRACTED ARTICLE: DDB1 and Cul4 are necessary for gene silencing and heterochromatin formation at pericentromeric regions in Neurospora
Yingqiong Cao, Jicheng Wei, Silu Yang, Jinquan Sun, Hui Xu, Ying Wang, Yuanbiao Zhao, Qun He
 doi: 10.1007/s13238-014-0067-7
Transcriptional mechanism of IRF8 and PU.1 governs microglial activation in neurodegenerative condition
Nan Zhou, Kaili Liu, Yue Sun, Ying Cao, Jing Yang
Microglial activation occurs in divergent neuropathological conditions. Such microglial event has the key involvement in the progression of CNS diseases. However, the transcriptional mechanism governing microglial activation remains poorly understood. Here, we investigate the microglial response to traumatic injuryinduced neurodegeneration by the 3D fluorescence imaging technique. We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation, as their specific post-developmental deletion in microglia abolishes the process. Mechanistically, we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhanced expression during microglial activation. Moreover, IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation-related genes. This action of cooperative transcription can be further verified biochemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA. Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition.
The structure differences of Japanese encephalitis virus SA14 and SA14-14-2 E proteins elucidate the virulence attenuation mechanism
Xinyu Liu, Xin Zhao, Rui Na, Lili Li, Eberhard Warkentin, Jennifer Witt, Xu Lu, Yongxin Yu, Yuquan Wei, Guohong Peng, Yuhua Li, Junzhi Wang
 doi: 10.1007/s13238-018-0551-6
Neuroendocrine characteristics of induced pluripotent stem cells from polycystic ovary syndrome women
Zheying Min, Yue Zhao, Jing Hang, Yun Ren, Tao Tan, Yong Fan, Yang Yu
Si-Ho Tchou: life of a legend from physiology to psychology
Wei Chen, Xi Chen, Shengjun Wen
 doi: 10.1007/s13238-018-0553-4
Cryo-EM structure of L-fucokinase/GDP-fucose pyrophosphorylase (FKP) in Bacteroides fragilis
Ying Liu, Huifang Hu, Jia Wang, Qiang Zhou, Peng Wu, Nieng Yan, Hong-Wei Wang, Jia-Wei Wu, Linfeng Sun
 doi: 10.1007/s13238-018-0576-x
Correction to: Prof. Huan-Yong Chen: a leading botanist and taxonomist, one of the pioneers and founders of modern plant taxonomy in China
Rui-Lan Huang
 doi: 10.1007/s13238-018-0569-9
Single senescent cell sequencing reveals heterogeneity in senescent cells induced by telomere erosion
Huanyin Tang, Anke Geng, Tengjiao Zhang, Chen Wang, Ying Jiang, Zhiyong Mao
 doi: 10.1007/s13238-018-0591-y
Crystal structure of Lamellipodin implicates diverse functions in actin polymerization and Ras signaling
Yu-Chung Chang, Hao Zhang, Mark L. Brennan, Jinhua Wu
 doi: 10.1007/s13238-012-2082-x
The adapter protein Lamellipodin (Lpd) plays an important role in cell migration. In particular, Lpd mediates lamellipodia formation by regulating actin dynamics via interacting with Ena/VASP proteins. Its RA-PH tandem domain configuration suggests that like its paralog RIAM, Lpd may also mediate particular Ras GTPase signaling. We determined the crystal structures of the Lpd RA-PH domains alone and with an N-terminal coiled-coil region (cc-RA-PH). These structures reveal that apart from the anticipated coiled-coil interaction, Lpd may also oligomerize through a second intermolecular contact site. We then validated both oligomerization interfaces in solution by mutagenesis. A fluorescence-polarization study demonstrated that Lpd binds phosphoinositol with low affinity. Based on our crystallographic and biochemical data, we propose that Lpd and RIAM serve diverse functions:Lpd plays a predominant role in regulating actin polymerization, and its function in mediating Ras GTPase signaling is largely suppressed compared to RIAM.
Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury
Dandan Luo, Weihong Ge, Xiao Hu, Chen Li, Chia-Ming Lee, Liqiang Zhou, Zhourui Wu, Juehua Yu, Sheng Lin, Jing Yu, Wei Xu, Lei Chen, Chong Zhang, Kun Jiang, Xingfei Zhu, Haotian Li, Xinpei Gao, Yanan Geng, Bo Jing, Zhen Wang, Changhong Zheng, Rongrong Zhu, Qiao Yan, Quan Lin, Keqiang Ye, Yi E. Sun, Liming Cheng
 doi: 10.1007/s13238-018-0559-y
The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.
Cryo-EM structure of an early precursor of large ribosomal subunit reveals a half-assembled intermediate
Dejian Zhou, Xing Zhu, Sanduo Zheng, Dan Tan, Meng-Qiu Dong, Keqiong Ye
 doi: 10.1007/s13238-018-0526-7
Assembly of eukaryotic ribosome is a complicated and dynamic process that involves a series of intermediates. It is unknown how the highly intertwined structure of 60S large ribosomal subunits is established. Here, we report the structure of an early nucleolar pre-60S ribosome determined by cryo-electron microscopy at 3.7 Å resolution, revealing a half-assembled subunit. Domains I, Ⅱ and VI of 25S/5.8S rRNA pack tightly into a native-like substructure, but domains Ⅲ, IV and V are not assembled. The structure contains 12 assembly factors and 19 ribosomal proteins, many of which are required for early processing of large subunit rRNA. The Brx1-Ebp2 complex would interfere with the assembly of domains IV and V. Rpf1, Mak16, Nsa1 and Rrp1 form a cluster that consolidates the joining of domains I and Ⅱ. Our structure reveals a key intermediate on the path to establishing the global architecture of 60S subunits.
Weisun Tao: a pioneer of biochemistry in China
Tianwei He
 doi: 10.1007/s13238-017-0383-9
Engineering vascularized skeletal muscle tissue with transcriptional factor ETV2-induced autologous endothelial cells
Guanrong Yan, Ruibin Yan, Cheng Chen, Yanqiu Zhao, Wei Qin, Matthew B. Veldman, Song Li, Shuo Lin
 doi: 10.1007/s13238-018-0542-7
Cells derived from iPSC can be immunogenic-Yes or No?
Jiani Cao, Xiaoyan Li, Xiao Lu, Chao Zhang, Honghao Yu, Tongbiao Zhao
 doi: 10.1007/s13238-013-3909-9
The induced pluripotent stem cells (iPSCs), derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. However, our recent studies have found that even syngeneic iPSC-derived cells can be immunogenic in syngeneic hosts by using a teratoma transplantation model (Zhao et al., 2011). Recently two research groups differentiated the iPSCs into different germ layers or cells, transplanted those cells to the syngeneic hosts, and evaluated the immunogenicity of those cells. Both of the two studies support our conclusions that some certain but not all tissues derived from iPSCs can be immunogenic, although they claimed either "negligible" or "lack of" immunogenicity in iPSC derivatives (Araki et al., 2013; Guha et al., 2013). To test the immunogenicity of clinically valuable cells differentiated from human iPSCs are emergently required for translation of iPSC technology to clinics.
Structural insights into the species preference of the influenza B virus NS1 protein in ISG15 binding
Yinan Jiang, Xinquan Wang
Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrow-derived macrophage
Yali Jiang, Yuanyuan Wang, Pengfei Ma, Dongjie An, Junlong Zhao, Shiqian Liang, Yuchen Ye, Yingying Lu, Peng Zhang, Xiaowei Liu, Hua Han, Hongyan Qin
 doi: 10.1007/s13238-018-0527-6
Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.
In vivo tunable CRISPR mediates efficient somatic mutagenesis to generate tumor models
Xiaomeng An, Linlin Li, Sen Wu
In memory of Prof. C. C. Li
Zhi Xia, Juan Tian, Xiaoling Wang, Huanming Yang
Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun
Wei Shao, Shasha Li, Lu Li, Kequan Lin, Xinhong Liu, Haiyan Wang, Huili Wang, Dong Wang
 doi: 10.1007/s13238-018-0533-8
Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for antimetastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models. Mechanistically, Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein. Notably, JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients. Collectively, we established a novel approach for the discovery of anti-metastatic drugs, identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM. Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
Channel activity of mirror-image M2 proton channel of influenza A virus is blocked by achiral or chiral inhibitors
Qing-Yan Guo, Long-Hua Zhang, Chao Zuo, Dong-Liang Huang, Zhipeng A. Wang, Ji-Shen Zheng, Chang-Lin Tian
 doi: 10.1007/s13238-018-0536-5
Zing-Yang Kuo and behavior epigenesis based on animal experiments
Yanyan Qian, Wei Chen, Benyu Guo
 doi: 10.1007/s13238-018-0516-9
Remodeling of host membranes during herpesvirus assembly and egress
Ying Lv, Sheng Zhou, Shengyan Gao, Hongyu Deng
 doi: 10.1007/s13238-018-0577-9
Many viruses, enveloped or non-enveloped, remodel host membrane structures for their replication, assembly and escape from host cells. Herpesviruses are important human pathogens and cause many diseases. As large enveloped DNA viruses, herpesviruses undergo several complex steps to complete their life cycles and produce infectious progenies. Firstly, herpesvirus assembly initiates in the nucleus, producing nucleocapsids that are too large to cross through the nuclear pores. Nascent nucleocapsids instead bud at the inner nuclear membrane to form primary enveloped virions in the perinuclear space followed by fusion of the primary envelopes with the outer nuclear membrane, to translocate the nucleocapsids into the cytoplasm. Secondly, nucleocapsids obtain a series of tegument proteins in the cytoplasm and bud into vesicles derived from host organelles to acquire viral envelopes. The vesicles are then transported to and fuse with the plasma membrane to release the mature virions to the extracellular space. Therefore, at least two budding and fusion events take place at cellular membrane structures during herpesviruses assembly and egress, which induce membrane deformations. In this review, we describe and discuss how herpesviruses exploit and remodel host membrane structures to assemble and escape from the host cell.
Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations
Fang Hu, Feng Liu
 doi: 10.1007/s13238-013-3077-y
It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissuespecific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.
Human germline editing: Insights to future clinical treatment of diseases
Yanni Li, Xiang Jin Kang, Jeremy Kah Sheng Pang, Boon Seng Soh, Yang Yu, Yong Fan
Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells
Dengwen Li, Xiaodong Sun, Linlin Zhang, Bing Yan, Songbo Xie, Ruming Liu, Min Liu, Jun Zhou
 doi: 10.1007/s13238-013-3098-6
Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class Ⅱ HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.
Tongue coating microbiome as a potential biomarker for gastritis including precancerous cascade
Jiaxing Cui, Hongfei Cui, Mingran Yang, Shiyu Du, Junfeng Li, Yingxue Li, Liyang Liu, Xuegong Zhang, Shao Li
 doi: 10.1007/s13238-018-0596-6
The development of gastritis is associated with an increased risk of gastric cancer. Current invasive gastritis diagnostic methods are not suitable for monitoring progress. In this work based on 78 gastritis patients and 50 healthy individuals, we observed that the variation of tongue-coating microbiota was associated with the occurrence and development of gastritis. Twenty-one microbial species were identified for differentiating tongue-coating microbiomes of gastritis and healthy individuals. Pathways such as microbial metabolism in diverse environments, biosynthesis of antibiotics and bacterial chemotaxis were up-regulated in gastritis patients. The abundance of Campylobacter concisus was found associated with the gastric precancerous cascade. Furthermore, Campylobacter concisus could be detected in tongue coating and gastric fluid in a validation cohort containing 38 gastritis patients. These observations provided biological evidence of tongue diagnosis in traditional Chinese medicine, and indicated that tongue-coating microbiome could be a potential non-invasive biomarker, which might be suitable for long-term monitoring of gastritis.
Shitsan Pai: the establishment of the first biophysics department in the world
Rui Liu
 doi: 10.1007/s13238-018-0557-0
Retraction Note to: DDB1 and Cul4 are necessary for gene silencing and heterochromatin formation at pericentromeric regions in Neurospora
Yingqiong Cao, Jicheng Wei, Silu Yang, Jinquan Sun, Hui Xu, Ying Wang, Yuanbiao Zhao, Qun He
 doi: 10.1007/s13238-014-0079-3
Effect of pH, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes
Yirui Cheng, Qingyu Zeng, Qing Han, Weiliang Xia
 doi: 10.1007/s13238-018-0529-4
Sialylation is involved in cell fate decision during development, reprogramming and cancer progression
Fenjie Li, Junjun Ding
Sialylation, or the covalent addition of sialic acid to the terminal end of glycoproteins, is a biologically important modification that is involved in embryonic development, neurodevelopment, reprogramming, oncogenesis and immune responses. In this review, we have given a comprehensive overview of the current literature on the involvement of sialylation in cell fate decision during development, reprogramming and cancer progression. Sialylation is essential for early embryonic development and the deletion of UDP-GlcNAc 2-epimerase, a rate-limiting enzyme in sialic acid biosynthesis, is embryonically lethal. Furthermore, the sialyltransferase ST6GAL1 is required for somatic cell reprogramming, and its downregulation is associated with decreased reprogramming efficiency. In addition, sialylation levels and patterns are altered during cancer progression, indicating the potential of sialylated molecules as cancer biomarkers. Taken together, the current evidences demonstrate that sialylation is involved in crucial cell fate decision.
Colonization process of Arabidopsis thaliana roots by a green fluorescent protein-tagged isolate of Verticillium dahliae
Pan Zhao, Yun-Long Zhao, Yun Jin, Tao Zhang, Hui-Shan Guo
 doi: 10.1007/s13238-013-3061-6
Chemical screen identifies a geroprotective role of quercetin in premature aging
Lingling Geng, Zunpeng Liu, Weiqi Zhang, Wei Li, Zeming Wu, Wei Wang, Ruotong Ren, Yao Su, Peichang Wang, Liang Sun, Zhenyu Ju, Piu Chan, Moshi Song, Jing Qu, Guang-Hui Liu
 doi: 10.1007/s13238-018-0567-y
Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
Developing potent PROTACs tools for selective degradation of HDAC6 protein
Zixuan An, Wenxing Lv, Shang Su, Wei Wu, Yu Rao
Loss-of-function of sox3 causes follicle development retardation and reduces fecundity in zebrafish
Qiang Hong, Cong Li, Ruhong Ying, Heming Lin, Jingqiu Li, Yu Zhao, Hanhua Cheng, Rongjia Zhou
Folliculogenesis is essential for production of female gametes in vertebrates. However, the molecular mechanisms underlying follicle development, particularly apoptosis regulation in ovary, remain elusive. Here, we generated sox3 knockout zebrafish lines using CRISPR/Cas9. sox3 knockout led to follicle development retardation and a reduced fecundity in females. Comparative analysis of transcriptome between sox3-/- and wild-type ovaries revealed that Sox3 was involved in pathways of ovarian steroidogenesis and apoptosis. Knockout of sox3 promoted follicle apoptosis and obvious apoptosis signals were detected in somatic cells of stages Ⅲ and IV follicles of sox3-/- ovaries. Moreover, Sox3 can bind to and activate the promoter of cyp19a1a. Up-regulation of Cyp19a1a expression promoted 17β-estradiol synthesis, which inhibited apoptosis in follicle development. Thus, Sox3 functions as a regulator of Cyp19a1a expression, via 17β-E2 linking apoptosis suppression, which is implicated in improving female fecundity.
Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter
Donghao Sun, Xuetao Cao, Chunmei Wang
Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a nontraditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.
Dgcr8 deletion in the primitive heart uncovered novel microRNA regulating the balance of cardiac-vascular gene program
Xi Chen, Lin Wang, Rujin Huang, Hui Qiu, Peizhe Wang, Daren Wu, Yonglin Zhu, Jia Ming, Yangming Wang, Jianbin Wang, Jie Na
 doi: 10.1007/s13238-018-0572-1
Primitive mammalian heart transforms from a single tube to a four-chambered muscular organ during a short developmental window. We found that knocking out global microRNA by deleting Dgcr8 microprocessor in Mesp1 cardiovascular progenitor cells lead to the formation of extremely dilated and enlarged heart due to defective cardiomyocyte (CM) differentiation. Transcriptome analysis revealed unusual upregulation of vascular gene expression in Dgcr8 cKO hearts. Single cell RNA sequencing study further confirmed the increase of angiogenesis genes in single Dgcr8 cKO CM. We also performed global microRNA profiling of E9.5 heart for the first time, and identified that miR-541 was transiently highly expressed in E9.5 hearts. Interestingly, introducing miR-541 back into microRNA-free CMs partially rescued their defects, downregulated angiogenesis genes and significantly upregulated cardiac genes. Moreover, miR-541 can target Ctgf and inhibit endothelial function. Our results suggest that microRNAs are required to suppress abnormal angiogenesis gene program to maintain CM differentiation.
Jiao Shao: A forerunner of physiological psychology and comparative psychology in China
Lijun Wang, Yanyan Qian, Yanjie Su
5' capped and 3' polyA-tailed sgRNAs enhance the efficiency of CRISPR-Cas9 system
Wei Mu, Yongping Zhang, Xutong Xue, Lei Liu, Xiaofei Wei, Haoyi Wang
 doi: 10.1007/s13238-018-0552-5
Tonghua Liu: A life dedicated to clinical pathology
Lin Dong, Tanping Fu, Junyi Pang, Zhiyong Liang, Wenli Duan
IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes
Cécile Apert, Paola Romagnoli, Joost P. M. van Meerwijk
 doi: 10.1007/s13238-017-0425-3
Immunosuppressive regulatory T lymphocytes (Treg) expressing the transcription factor Foxp3 play a vital role in the maintenance of tolerance of the immunesystem to self and innocuous non-self. Most Treg that are critical for the maintenance of tolerance to self, develop as an independent T-cell lineage from common T cell precursors in the thymus. In this organ, their differentiation requires signals from the T cell receptor for antigen, from co-stimulatory molecules, as well as from cytokine-receptors. Here we focus on the cytokines implicated in thymic development of Treg, with a particular emphasis on the roles of interleukin-2 (IL-2) and IL-15. The more recently appreciated involvement of TGF-β in thymic Treg development is also briefly discussed. Finally, we discuss how cytokine-dependence of Treg development allows for temporal, quantitative, and potentially qualitative modulation of this process.
Chia-Chen Tan and genetics in modern China
Lei Fu
 doi: 10.1007/s13238-018-0539-2
Correction to: Gene activation in human cells using CRISPR/Cpf1-p300 and CRISPR/Cpf1-SunTag systems
Xin Zhang, Wei Wang, Lin Shan, Le Han, Shufeng Ma, Yan Zhang, Bingtao Hao, Ying Lin, Zhili Rong
Correction to: Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity
Bo Jing, Chunxue Zhang, Xianjun Liu, Liqiang Zhou, Jiping Liu, Yinan Yao, Juehua Yu, Yuteng Weng, Min Pan, Jie Liu, Zuolin Wang, Yao Sun, Yi Eve Sun
 doi: 10.1007/s13238-018-0574-z
Retraction Note: Cryptomycota: the missing link
Krishna Bolla, Elizabeth Jane Ashforth
 doi: 10.1007/s13238-012-2820-0
Professor Ju-Chi Li, one of the pioneers and founders of modern genetics in China
He Zhang
 doi: 10.1007/s13238-017-0487-2
Screening for mutations in human cardiomyopathy- is RBM24 a new but rare disease gene?
Anna Gaertner, Andreas Brodehl, Hendrik Milting
A 110-year-old wise man: Professor Libin T. Cheng, one of the founders of biochemistry and nutrition in China
He Zhang
 doi: 10.1007/s13238-017-0428-0
Down-regulation of the let-7i facilitates gastric cancer invasion and metastasis by targeting COL1A1
Yue Shi, Zipeng Duan, Xun Zhang, Xiaotian Zhang, Guoqing Wang, Fan Li
 doi: 10.1007/s13238-018-0550-7
Professor Li-Pin. King: a famous physiologist in China
Wei Gong, Fangfang Wang, Yike Ying
Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy
Lin Cao, Jizheng Chen, Yaxin Wang, Yuting Yang, Jie Qing, Zihe Rao, Xinwen Chen, Zhiyong Lou
 doi: 10.1007/s13238-018-0521-z
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT2AR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HT2AR and clinically available 5-HT2AR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDAapproved 5-HT2AR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.
Professor Tafu Yu: an eminent agricultural scientist and outstanding educator of our nation
Shuang Zhao, Tiantian Xu, Hexiang Wang
 doi: 10.1007/s13238-017-0494-3
RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy
Jing Liu, Xu Kong, Mengkai Zhang, Xiao Yang, Xiuqin Xu
 doi: 10.1007/s13238-018-0578-8
RNA splicing contributes to a broad spectrum of posttranscriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.
Phosphorylation of PLIN3 by AMPK promotes dispersion of lipid droplets during starvation
Jianxi Zhu, Mingyang Xu, Yi Liu, Lisha Zhuang, Kejun Ying, Feng Liu, Dan Liu, Wenbin Ma, Zhou Songyang
 doi: 10.1007/s13238-018-0593-9
Reciprocal regulation between lunapark and atlastin facilitates ER three-way junction formation
Xin Zhou, Yu He, Xiaofang Huang, Yuting Guo, Dong Li, Junjie Hu
Three-way junctions are characteristic structures of the tubular endoplasmic reticulum (ER) network. Junctions are formed through atlastin (ATL)-mediated membrane fusion and stabilized by lunapark (Lnp). However, how Lnp is preferentially enriched at three-way junctions remains elusive. Here, we showed that Lnp loses its junction localization when ATLs are deleted. Reintroduction of ATL1 R77A and ATL3, which have been shown to cluster at the junctions, but not wild-type ATL1, relocates Lnp to the junctions. Mutations in the N-myristoylation site or hydrophobic residues in the coiled coil (CC1) of Lnp N-terminus (NT) cause mis-targeting of Lnp. Conversely, deletion of the lunapark motif in the C-terminal zinc finger domain, which affects the homooligomerization of Lnp, does not alter its localization. Purified Lnp-NT attaches to the membrane in a myristoylation-dependent manner. The mutation of hydrophobic residues in CC1 does not affect membrane association, but compromises ATL interactions. In addition, Lnp-NT inhibits ATL-mediated vesicle fusion in vitro. These results suggest that CC1 in Lnp-NT contacts junction-enriched ATLs for proper localization; subsequently, further ATL activity is limited by Lnp after the junction is formed. The proposed mechanism ensures coordinated actions of ATL and Lnp in generating and maintaining three-way junctions.
Optic tectal superficial interneurons detect motion in larval zebrafish
Chen Yin, Xiaoquan Li, Jiulin Du
 doi: 10.1007/s13238-018-0587-7
Detection of moving objects is an essential skill for animals to hunt prey, recognize conspecifics and avoid predators. The zebrafish, as a vertebrate model, primarily uses its elaborate visual system to distinguish moving objects against background scenes. The optic tectum (OT) receives and integrates inputs from various types of retinal ganglion cells (RGCs), including direction-selective (DS) RGCs and size-selective RGCs, and is required for both prey capture and predator avoidance. However, it remains largely unknown how motion information is processed within the OT. Here we performed in vivo whole-cell recording and calcium imaging to investigate the role of superficial interneurons (SINs), a specific type of optic tectal neurons, in motion detection of larval zebrafish. SINs mainly receive excitatory synaptic inputs, exhibit transient ON-or OFF-type of responses evoked by light flashes, and possess a large receptive field (RF). One fifth of SINs are DS and classified into two subsets with separate preferred directions. Furthermore, SINs show size-dependent responses to moving dots. They are efficiently activated by moving objects but not static ones, capable of showing sustained responses to moving objects and having less visual adaptation than periventricular neurons (PVNs), the principal tectal cells. Behaviorally, ablation of SINs impairs prey capture, which requires local motion detection, but not global looming-evoked escape. Finally, starvation enhances the gain of SINs' motion responses while maintaining their size tuning and DS. These results indicate that SINs serve as a motion detector for sensing and localizing sized moving objects in the visual field.
Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferas
Jinbo Huang, Xu Dong, Zhou Gong, Ling-Yun Qin, Shuai Yang, Yue-Ling Zhu, Xiang Wang, Delin Zhang, Tingting Zou, Ping Yin, Chun Tang
 doi: 10.1007/s13238-018-0518-7
N6-methyladenosine (m6A), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without. The ZFD thus serves as the target recognition domain, a structural feature previously shown for DNA methyltransferases, and cooperates with the MTDs of METTL3-METTL14 for catalysis. However, the interaction between the ZFD and the specific RNA is extremely weak, with the binding affinity at several hundred micromolar under physiological conditions. The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel β-sheet. Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface. As a division of labor, the RNAbinding interface comprises basic residues from zinc finger 1 and hydrophobic residues from β-sheet and zinc finger 2. Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded, which may permit the cooperation between the two domains during catalysis. Together, the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA m6A modification.
Structural basis of AimP signaling molecule recognition by AimR in Spbeta group of bacteriophages
Xiangkai Zhen, Huan Zhou, Wei Ding, Biao Zhou, Xiaolong Xu, Vanja Perčulija, Chun-Jung Chen, Ming-Xian Chang, Muhammad Iqbal Choudhary, Songying Ouyang
 doi: 10.1007/s13238-018-0588-6
Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch
Daisuke Aki, Qian Li, Hui Li, Yun-Cai Liu, Jee Ho Lee
 doi: 10.1007/s13238-018-0586-8
Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.
The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1-and Pgc-1α-mediated regulation of Glut2
Xinhui Wang, Hong Gao, Wenhui Wu, Enjun Xie, Yingying Yu, Xuyan He, Jin Li, Wanru Zheng, Xudong Wang, Xizhi Cao, Zhuoxian Meng, Ligong Chen, Junxia Min, Fudi Wang
Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.
Correction to: Efficient derivation of extended pluripotent stem cells from NOD-scid Il2rg-/- mice
Yaqin Du, Ting Wang, Jun Xu, Chaoran Zhao, Haibo Li, Yao Fu, Yaxing Xu, Liangfu Xie, Jingru Zhao, Weifeng Yang, Ming Yin, Jinhua Wen, Hongkui Deng
 doi: 10.1007/s13238-018-0571-2
Recently we have established a new culture condition enabling the derivation of extended pluripotent stem (EPS) cells, which, compared to conventional pluripotent stem cells, possess superior developmental potential and germline competence. However, it remains unclear whether this condition permits derivation of EPS cells from mouse strains that are refractory or non-permissive to pluripotent cell establishment. Here, we show that EPS cells can be robustly generated from non-permissive NOD-scid Il2rg-/- mice through de novo derivation from blastocysts. Furthermore, these cells can also be efficiently generated by chemical reprogramming from embryonic NOD-scid Il2rg-/- fibroblasts. NOD-scid Il2rg-/- EPS cells can be expanded for more than 20 passages with genomic stability and can be genetically modified through gene targeting. Notably, these cells contribute to both embryonic and extraembryonic lineages in vivo. More importantly, they can produce chimeras and integrate into the E13.5 genital ridge. Our study demonstrates the feasibility of generating EPS cells from refractory mouse strains, which could potentially be a general strategy for deriving mouse pluripotent cells. The generation of NOD-scid Il2rg-/- EPS cell lines permits sophisticated genetic modification in NOD-scid Il2rg-/- mice, which may greatly advance the optimization of humanized mouse models for biomedical applications.
Terminal transfer amplification and sequencing for high-efficiency and lowbias copy number profiling of fragmented DNA samples
Dongqing Jiang, Xiannian Zhang, Yuhong Pang, Jianyun Zhang, Jianbin Wang, Yanyi Huang
 doi: 10.1007/s13238-018-0540-9
TLE4 acts as a corepressor of Hes1 to inhibit inflammatory responses in macrophages
Xiang Zhang, Xiaoyu Li, Fei Ning, Yingli Shang, Xiaoyu Hu
 doi: 10.1007/s13238-018-0554-3
Current issue
  • ISSN1674-800X
  • EISSN1674-8018
  • IF (2017) 6.228

Microbiota and Human Health

May 2018
Volume 9
Issue 5
pp: 395-510

Metabolism and Disease

May 2018
Volume 9
Issue 2
pp: 141-237

Therapeutic Antibodies

May 2018
Volume 9
Issue 1
pp: 1-139


Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang Beijing 100101, China

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