Abstract: Mechanisms for scaling organs are essential to control the contribution of stem and progenitor cells. For animals that regenerate, their tissue restoration involves coordinating rapid allometric (disproportional to the body) growth of stem/progenitor cells with the reinstatement of isometric (proportional to the body) growth once the correct dimensions of the regenerating organ are reached. Calcineurin inhibition results in continued allometric outgrowth of regenerating fins beyond their original dimensions. Congruent with these results, calcineurin activity is low when the rate of progenitor cell proliferation is highest and growth is allometric, and its activity increases as the regeneration rate returns to isometric growth. Furthermore, inhibition of calcineurin in uninjured adult fins switches isometric growth into allometric growth for tissue regeneration, demonstrating that calcineurin regulates appendage allometry. Furthermore, we provide evidence that calcineurin is regulating proportional growth by regulating the activity of the potassium leak channel Kcnk5b, whose activity has been shown to promote allometric growth. In summary, we identified a calcineurin-mediated mechanism that operates as a molecular switch between distal isometric growth and proximal allometric growth and may do so by regulating bioelectric signaling of tissues.
Christopher ANTOS Associate Professor, ShanghaiTech University
The Antos group researches tissue regeneration. To understand the biology of regeneration, Dr. Antos is interested in answering three fundamental questions:
1. How are cells at the site of injury induced to regenerate lost tissues?
2. How are cells involved in regeneration controlled to produce the correct pattern?
3. What stops regeneration once the appropriate size is reached?
These questions are highly relevant to tissue bioengineering and to the stem cell biology of repair or reconstruction of human tissues. The Antos lab uses the zebrafish to answer these questions, because the zebrafish will regenerate many of its organs, including heart and appendages. Therefore, the lab can describe and dissect the cell and molecular mechanisms involved in the fish’s regeneration abilities and relate them to the limits on mammalian regeneration.
Abstract: Brain function is based on neuron-to-neuron communication called synaptic transmission. Synaptic transmission is mediated by releasing of neurotransmitter from presynaptic neurons and activation of neurotransmitter receptors on postsynaptic neurons. Glutamate is the major excitatory neurotransmitter in mammalian brain. NMDA receptor is a class of glutamate-gated ion channel involved in many important brain functions. For example, NMDA receptor hypofunction underlies illnesses such as schizophrenia and Alzheimer's disease. Therefore potentiation of its activity could be a novel strategy to treat these diseases. However it has been impossible to test this hypothesis because NMDA receptor agonists lead to activation of extrasynaptic NMDA receptors, resulting immediate excitotoxicity and neuronal death. To tackle this question, we discovered positive allosteric modulators of NMDA receptors through target-oriented drug discovery, which could enhance NMDA receptor activity without causing neuronal toxicity because of its completely different pharmacological properties compared with agonists. Therefore these compounds have therapeutic potentials as conceptually novel treatments for certain devastating brain diseases.
Yelin CHEN Researcher, IRCBC, CAS
Abstract: Electrical transmission through gap junctions is a vital mode of intercellular communication in many tissues and defects in gap junction formation and/or function are the cause of at least 10 human pathological conditions. However, progress in identifying signals or scaffolding molecules that regulate gap junction formation has been slow. So far, most of the gap junction proteome has been established through a combination of studies involving CoIP, co-localization, co-fractionation, yeast two-hybrid assays and cell-free affinity binding studies. It was previously uncertain whether a genetically accessible system could be used to discover gap junction regulatory molecules because of the non-conservation between vertebrate connexins and invertebrate connexins (innexins). We previously showed that gap junctions are formed between BDU interneurons and PLM mechanoreceptors in C. elegans and the connectivity of BDU with PLM is influenced by Wnt signaling. From a genetic screen searching for mutants with altered gap junction distribution, we further identified multiple signaling pathways involved in gap junction formation in vivo. Currently, we are utilizing mouse model to investigate the conserved role of above molecules. Based upon our studies, we believe that unbiased genetic screens with innexin proteins in worms or even flies could facilitate the identification of gap junction regulatory molecules in general.
Mei DING Researcher, IGDB, CAS
Research Area : Neural Development
Research interestsThe simple nervous system of the nematode C. elegans is well suited for studying neural development. The complete synaptic connectivity of the nervous system is known from reconstructions of serial sections of electron micrographs, allowing the analysis to be carried out at the level of a single cell and single synapse. Furthermore, the use of fluorescent protein facilitates the visualization of neuronal processes and synapses in vivo and in living animals. We are studying the development of neural circuits by characterizing pathways for axon outgrowth, synapse specificity, and synaptogenesis.
Abstract: We study the function and mechanism of microRNAs, RNA-binding proteins, and translational control in the immune system, focusing on their roles in lymphocyte development and differentiation, immune tolerance and autoimmune disease, antibody response, antiviral response, antitumor response, lymphoma, and leukemia. In the past ten years, we made a series of original findings and published more than 30 papers in journals including Cell, Science, Nature Immunology, Immunity, J Exp Med, Nature Communications, Genes & Development, EMBO J, Leukemia, and PLoS Genetics. Google Scholar shows that papers from our group have been cited for more than 6,000 times.
Changchun XIAO Professor, Xiamen University
本实验室主要从事microRNA (miRNA), RNA结合蛋白 （RBP）和翻译调控在免疫系统中的功能与机理研究，着眼于阐明它们在淋巴细胞发育，免疫耐受和自身免疫病，免疫应答，抗体反应，抗病毒反应，抗肿瘤反应，淋巴细胞恶性转化，淋巴癌以及白血病发病机理中的功能和作用机理。过去十余年来，取得了一批原创性科研成果，共发表论文30余篇（包括Cell, Science, Nature Immunology, Immunity, J Exp Med, Nature Communications, Genes & Development, EMBO J, Leukemia)，累计引用达6000余次，其中过去五年被引用3500余次(基于Google Scholar).
Abstract: DNA phosphoester bonds are exceedingly resistant to hydrolysis in the absence of chemical or enzymatic catalysts. This property is particularly important for organisms with large genomes, as resistance to hydrolytic degradation permits the long-term storage of genetic information. Here we report the creation and analysis of two classes of engineered deoxyribozymes (DNA enzymes) that selectively and rapidly hydrolyze DNA. Members of class I deoxyribozymes carry a catalytic core composed of only 15 conserved nucleotides and attain an observed rate constant (kobs) of ~1 min-1 when incubated near neutral pH in the presence of Zn2+. Natural DNA sequences conforming to the class I consensus sequence and structure were found that undergo hydrolysis under selection conditions (2 mM Zn2+, pH 7), which demonstrates that the inherent structure of certain DNA regions might promote catalytic reactions leading to genomic instability. Engineered DNA molecules that encode a class I self-hydrolyzing deoxyribozyme have been successfully used as templates for rolling circle amplification (RCA) to produce single-stranded DNAs (ssDNAs) of single- and multiple-unit lengths. We expect that these hydrolytic deoxyribozymes could be useful elements for the creation of novel systems in DNA Nanotechnology and Synthetic Biology.
Hongzhou GU Professor, Fudan University
本实验室致力于DNA纳米技术，DNA/RNA分子传感器的组装，功能性的DNA/RNA分子的体外筛选，以及药物小分子筛选等相关研究。迄今已有多篇论文发表在相关领域的顶级刊物上，其中包括Nature, Nature Nanotechnology, Journal of the American Chemical Society, Analytical Chemistry, ACS Chemical Biology等学术杂志。
Abstract: Liver regeneration happens after various types of injuries. Unlike the well-studied liver regeneration caused by partial hepatectomy, there is accumulating evidence suggesting that liver regeneration during other injuries may result from some unknown mechanism. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of carbon tetrachloride (CCl4). However, it was not observed during the early phase of acute liver injuries after partial hepatectomy or single treatment of CCl4. Remarkably, most of IGF-2 expressing hepatocytes were located at the histological area around the central vein of liver lobule after the liver injuries caused either in Fah-deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by the induced IGF-2 over-expression, which could be inhibited by AAV-delivered IGF-2 shRNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 via both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to co-localize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. Conclusion: IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs after partial hepatectomy.
Pengyu HUANG Assitant Professor, PI, ShanghaiTech University
Abstract: In synthetic biology, building complex logic circuits are often difficult, especially in a single cell population. It requires many non-crosstalking information processing units such as quorum sensing (QS) factors, to work within a cell without significant interference. However, these non-crosstalking QS factors are very limited. Furthermore, even for simple circuits, one has to create de novo which can be difficult for beginners. It would be ideal to use modularized parts assemble directly into circuits. Therefore, we aimed to create a multilayer signal-processing system by using compartmentalized QS factors. We have provided proof-of-concept data and modeling to show that our system would allow faithful information flow between bacterial population. Also, we aimed to build QS part libraries to allow easily switching of parts, changing signal inputs and outputs without de novo cloning. Thus, our system may not only increase signal-processing power, but also make it friendlier to synthetic biologists.
iGEM ShanghaiTech2017 Student Group, ShanghaiTech University
Abstract: In adult life, many organs rely on stem cells to maintain their integrity by replenishing lost cells during tissue homeostasis and regeneration, yet the regulatory mechanisms that control stem cell proliferation, self-renewal and differentiation are not fully understood. We are studying these mechanisms using Drosophila adult midgut as a model system. We find that the Hippo tumor suppressor pathway restricts intestinal stem cell (ISC) proliferation through both cell autonomous and non-cell autonomous mechanisms. We have demonstrated that epithelium-derived BMP serve as a niche signal to promote ISC self-renewal in the midgut. Decapentaplegic (Dpp) and Glass-bottom boat (Gbb) are produced by enterocytes with Dpp exhibiting basal enrichment, and that Dpp and Gbb act in conjunction to promote ISC fate by antagonizing Notch-mediated differentiation. Extracellular matrix proteins at the basement membrane regulate ISC self-renewal by controlling the range of BMP signaling. Furthermore, epithelial damage increases BMP production and signaling, leading to increased ISC population and rapid midgut regeneration. The employment of midgut epithelium as a niche for stem cell self-renewal may provide a mechanism for direct communication between the stem cell niche and the environment, allowing niche signal production and stem cell pool size to be fine-tuned in response to physiological and pathological stimuli.
Jin JIANG Professor, University of Texas
Cell-cell communication (cell signaling) is a fundamental and prevalent mechanism that controls cell growth, cell fate determination and pattern formation of multicellular organisms. We are interesting in studying how inductive signals are generated and interpreted by cells, and how misregulation of cell signaling may cause diseases such as cancer. We have been carrying out systematic genetic screens to identify genes controlling pattern formation and growth of Drosophila adult organs. For example, we have identified many novel components in the Hh, Wg and other signaling pathways. We are also interested in understanding how cell growth and organ size are regulated and how growth and patterning are coordinated. Finally, we are interested in the mechanisms that control adult stem cell proliferation, tissue homeostasis and regeneration.
Abstract: Non-genetic cell-to-cell variability often plays an important role for the survival of a clonal population when facing fluctuating environments. However, the underlying mechanisms regulating such non-genetic heterogeneity remain elusive in most organisms. In our lab, we find that a clonal yeast population exhibits morphological heterogeneity when Hsp90, a molecular chaperone, is reduced. The heterogeneity is driven by the dosage of two key regulators (Cdc28 and Cla4) of cell morphogenesis. Low Hsp90 levels reduce protein stability of these regulators and cause a sub-population of cells to switch to a filamentous form that has been previously suggested to be beneficial under certain hostile environments. Moreover, Hsp90-dependent morphological heterogeneity can be induced by environmental stress and is conserved across diverse yeast species. Our data suggest that Hsp90 provides an evolutionarily conserved mechanism that links environmental stress to the induction of morphological diversity. Because low-Hsp90 cells or organisms often reveal phenotypic heterogeneity, we speculate that Hsp90 may control a variety of physiological pathways in a manner similar to cell morphogenesis. By analyzing the proteome of low-Hsp90 cells, we further observed that the down-regulated proteins are highly conserved and assume central roles in cellular networks with a high number of protein interacting partners. Our results suggest that Hsp90 buffers genetic and non-genetic variation through regulating protein network hubs.
Jun-Yi LEU Research Fellow, IMB, Academia Sinica
Molecular mechanisms of speciation and genetic buffering
I. Genetic incompatibility and speciation
Speciation generates discrete populations, which in turn play an important role for maintaining novel adaptations during evolution. Hybrids between different species are usually inviable or sterile. One of the possible mechanisms causing postzygotic reproductive isolation is incompatibility between genes (speciation genes) from different species. These speciation genes are hypothesized to be some interacting components that cannot function properly when mixed with alleles from different species. Evolution of speciation genes is generally thought to be driven by adaptive evolution. Identifying these genes will provide more information about how speciation occurs.
Our lab uses a few closely related yeast species (the Saccharomyces sensu stricto complex) to identify genetic incompatibility leading to hybrid breakdown. By dissecting the molecular mechanisms of genetic incompatibility, we aim to know the common principles underlying yeast speciation and the driving forces behind the evolution of speciation genes.
II. Experimental evolution and genomic analysis of genetic buffering
Genetic buffering is the mechanism that suppresses phenotypic variation under normal conditions and releases this variation when its function is compromised. Buffering systems are crucial in protecting developmental processes from environmental and genetic perturbations. In addition, buffering systems may play an important role in setting the tempo of evolution since they can moderate these perturbations or help a population accumulate genetic variations essential for selection.
Although the concept of genetic buffering is well established, the mechanisms underlying genetic buffering are largely unclear. In our lab, a systematic approach combining experimental evolution and genomic analysis is used to understand the molecular basis of genetic buffering.
Abstract: The Drosophila gut is an ideal system to study stem cell biology because while it is simpler than that in mammals, it is highly similar at cellular and molecular levels. For example, Notch pathway functions similar in mammals and Drosophila to drive the differentiation of stem cell into either absorptive or secretory cells. To find novel molecular that module stem cells behavior, we generate a new collection of transgenic RNAi library and performed a pilot screen. we found CG6990 is required to control Notch signaling in Drosophila midgut. Depletion of CG6990 leads to gut stem cells hyperproliferation, while overexpression reduces the number of enteroendocrine cells, which exactly resembles the phenotype from the defect of Notch signaling. Finally, we confirmed the role of CG6990 in other somatic tissues.
Jianquan NI Professor, Tsinghua University
Abstract: Cellular aging (or senescence) has been viewed as a tumor suppression mechanism and also contributes to individual aging. Recent studies discovered widespread shortening of 3’ untranslated regions (3’ UTRs) in messenger RNA by alternative polyadenylation (APA) in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tend to use distal polyA sites (pA), leading to a global lengthening of 3’UTRs and reduced gene expression. A member of the cleavage stimulation factors CSTF2 was found to mediate the global lengthening of 3’ UTRs. Genes that harbor longer 3’ UTRs in senescent mouse and rat cells are enriched in common senescence-related pathways. Rras2, a member of the Ras superfamily participating in multiple signal transduction pathways and regulation of actin cytoskeleton, prefers longer 3’ UTR usage and exhibits decreased expression in senescent cells. Depletion of Rras2 promotes senescence, while rescue of Rras2 reverses senescence-associated phenotypes. Mechanistically, splicing factor TRA2B binds to core motif ‘AGAA’ located at alternative 3’ UTR of Rras2, reduces RRAS2 protein level and causes senescence. Both proximal and distal polyA signals show strong sequence conservation, including the ‘AGAA’ motif, highlighting the vital role of APA regulation during evolution. Our results reveal a novel mechanism through which APA controls senescence associated protein level, thereby contributing to cellular senescence.
Ting NI Professor, Fudan University
Abstract: Asymmetric stem cell division establishes an initial difference between a stem cell and its differentiating sibling, critical for maintaining homeostasis and preventing carcinogenesis. Yet the mechanisms that consolidate and lock in such initial fate bias remain obscure. Our laboratory uses fast-cycling Drosophila neural stem cells as a model system to tackle this question. Combining live imaging with genetic, molecular and biochemical approaches, we recently made an unexpected discovery that the super elongation complex (SEC), best known for transcription elongation checkpoint control, acts as an intrinsic amplifier to drive neural stem cell fate commitment. SEC is highly and specifically expressed in fly neural stem cells, where it promotes self-renewal by physically associating with Notch transcription activation complex and enhancing HES gene transcription. HES in turn upregulates SEC activity, forming a self-reinforcing positive feedback loop with SEC. SEC inactivation leads to neural stem cell loss, whereas its forced activation results in neural progenitor dedifferentiation and tumorigenesis. Our studies unveil an SEC-mediated intracellular amplifier mechanism in ensuring robustness and precision in stem cell fate commitment and provide mechanistic explanation for the highly frequent association of SEC overactivation with human cancers.
Yan SONG Investigator, Peking University
The main research interest of my laboratory focuses on the understanding of cellular and molecular mechanisms underlying self-renewal, migration and differentiation of normal and cancer stem cells. Stem cells yield promise for regenerative medicine but also pose huge challenges. It remains uncertain how to inhibit stem-cell-derived tumor formation without harming normal stem cells. It is likewise unclear how directional stem cell migration, a critical step in tissue regeneration, is orchestrated. Using newly-established or previously-unexplored stem cell models in Drosophila, we employ a convergence of fly genetics, cell biology, biochemistry and in vivo imaging to investigate a few fundamental questions: 1) How normal stem cells within a specific tissue are maintained and how to distinguish normal from cancer stem cells? 2) During normal development and upon tissue injury, how guidance cues may be converted into physical movement of stem cells in a timely and directional manner? Since the fundamental principles we unravel using the relatively simple Drosophila stem cell models are likely to be conserved in mammals, our studies promise to provide new insights into anti-cancer therapy and regenerative medicine.
Abstract: More than 90 percent of cancer patents die from metastasis. Unfortunately, there is still no drug on the market to specifically target metastasis. One of barriers is no appropriate in vitro cell model to completely reflect the complicated process of metastasis. This limitation directly leads to the disability of phenotypic-based drug development approach, which dominates the pharmaceutical industry so far. To meet this challenge, we present here a high throughput screening approach to anti-metastatic drug identification by combining metastasis-associated gene expression signature and HTS2 technology (high throughput sequencing based high throughput screening). It is well known that expression of a group of genes is differentiated between primary and metastatic tumors, which could serve as a metastasis-associated gene expression signature. Our hypothesis is that if a compound could reverse the expression of signature genes effectively, it should be a potential candidate for anti-metastatic drugs. This approach is initially applied to breast cancer, where a signature of 18 genes associated with lung metastasis has been well established. After screening about 9,000 compounds, we identify RSC006, which can reverse the expression of 6 out of these 18 genes. Then, we confirm that RSC006 significantly inhibits the motility and mammosphere formation of breast cancer cells in vitro and lung metastasis in vivo. More importantly, we believe the novel approach we developed for anti-metastatic drug discovery could be potentially applied to a broad spectrum of cancers.
Dong WANG Investigator, Tsinghua University
My laboratory (Cancer and Genomics) is trying to understand the mechanisms underlying regulated gene expression and transcriptional programming/reprogramming in cancer cells during tumorigenesis by utilizing combined genomic, epigenomic and chemical genomic approaches. Current research projects in my laboratory include:
(1) Revealing genetic and epigenetic mechanisms underlying transcriptional reprogramming;
(2) Investigating roles of non-coding RNAs in regulated gene expression;
(3) Using chemical genetics approaches to identify small molecules against cancers;
Abstract: The switch between quiescence and proliferation is central for neurogenesis and its alteration is linked to neurodevelopmental disorders such as microcephaly. However, intrinsic mechanisms that reactivate Drosophila larval neural stem cells (NSCs) to exit from quiescence are not well established. Here we show that the spindle matrix complex containing Chromator (Chro) functions as a key intrinsic regulator of NSC reactivation downstream of extrinsic insulin/insulin-like growth factor signalling. Chro also prevents NSCs from re-entering quiescence at later stages. NSC-specific in vivo profiling has identified many downstream targets of Chro, including a temporal transcription factor Grainy head (Grh) and a neural stem cell quiescence-inducing factor Prospero (Pros). We show that spindle matrix proteins promote the expression of Grh and repress that of Pros in NSCs to govern their reactivation. Our data demonstrate that nuclear Chro critically regulates gene expression in NSCs at the transition from quiescence to proliferation.
Hongyan WANG Associate Professor, Deputy Director, Duke-NUS
Dr. Wang is a recipient of Singapore National Academy of Science Young Scientist Award (2008) and National Research Foundation (NRF) Research Fellowship (2009). The choice of self-renewal versus differentiation is a fundamental issue in stem cell and cancer biology. Recently, Drosophila melanogaster neural stem cells, larval brain neuroblasts, were emerged as an excellent model for study stem cell self-renewal and tumorigenesis. We are focused on identifying brain tumor suppressors and underlying mechanisms by which they prevent tumor formation in larval brains. Currently, we are interested in addressing the following key questions: What mutations trigger neural stem cells to become cancer stem cells? How asymmetric divisions of neural stem cells are regulated? What are the mechanisms that prevent more mature cells from dedifferentiating back into neural stem cells?
Abstract: The current dogma in ophthalmological research presumes the intraocular environment to be sterile. Using high-throughput sequencing technology, we analyzed 180 metagenomes of intraocular fluid from human patients with eye diseases and animals. We find that resident microbiota inhabits the intraocular cavities in all eyes. A disease-specific signature of the microbial community differentiates several intraocular diseases including Age-related macular degeneration (AMD). Importantly, we find that an AMD specific bacterium is highly enriched in the soft drusen, which induces activation of complement and retinal cell pyroptosis in vitro and in vivo. Our study suggests a link between microbiota and all eye diseases. In particular, our study identifies bacterial infection as the major etiology of AMD, and provides a novel direction for the diagnosis, treatment, and prevention of this leading blinding disease.
Lai WEI Professor, Sun Yat-sen University
我们实验室利用细胞及分子免疫学、转化性生物信息学方法，结合高通量测序技术和模式动物工具，通过对基因组，表观基因组以及微生物组等多种免疫组学研究探索免疫性眼病的病因，诊断和个性化治疗方法。魏来曾于美国NIH主持总金额452万美元的免疫性疾病表观遗传学病因及治疗的研究项目。获得过包括美国科学院国家科研理事会科研助理奖，李氏基金会杰出成就奖等十项奖励。在包括Nature， Nature Immunology， Immunity， PNAS等杂志发表SCI论文共51篇。论文总IF超过530，总引用超过3820次，单篇最高引用超过600次。拥有4项国际专利。
Abstract: Oscillatory signals, and their precise dynamic features, play a crucial role in regulating various cellular functions. It remains largely unclear how different parameters or architectures of the oscillatory circuit quantitatively determine the resulting waveform. To address this question, we constructed a synthetic oscillator in S. cerevisiae by reconstituting the human NF-κB system. This simple but robust circuit allows us to systematically explore the quantitative design principles of oscillatory waveforms. For a circuit with a single core negative feedback loop, we determined how parameters such as feedback strength, the stability of the negative regulator and the level of the positive regulator tune both the shape and the period of the waveform. By incorporating a second negative feedback loop, we found that we could enable frequency-only tuning of oscillatory waveforms, without altering amplitude. The design principles uncovered here will enable function-guided oscillatory waveform design for diverse synthetic biology applications.
Ping WEI Professor, Peking University
Abstract: CRISPR adaptation requires several specific processes, including selection of protospacer from invaders (plasmid or virus) and subsequent integration of this sequence into the host CRISPR array at the leader sequence end. In the past a few years, we have successfully established the first native Type I CRISPR-Cas system (also first in Archaea domain) that showed efficient adaptation to a purified virus. With this system, we have answered several important and long-standing open questions in the field of CRISPR adaptation, including the adaptation efficiency, integration specificity, and the self vs nonself discrimination mechanisms during the CRISPR adaptation. We showed that primed adaptation is a more favorable route relative to the intractable naïve adaptation, and appeared to be a major pathway of CRISPR adaptation. We also showed that 19 mutated PAMs elicited priming for type I-B, and 4 consensus PAMs functioned for interference, highlighting the plasticity with which the interference machinery can adapt to escape virus, and explaining how self-priming is specifically avoided. In addition, we revealed that the DNA motifs close to the center of the first repeat are important for spacer integration at the leader end. These insights, together with our recently revealed interference mechanisms, have already helped us in developing novel genome editing tools in haloarchaea, and established a basis for further research of the molecular mechanism of CRISPR-Cas systems.
Hua XIANG Researcher, Inst of Microbio, CAS
Prof. Dr. Hua Xiang graduated with his Bachelor's degree in Biology (1991) and Master's degree in Genetics (1994) from Beijing Normal University, later he got his PhD in Biochemistry and Molecular Biology (1997) from Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC). He worked as postdoctoral fellow at University of Medicine & Dentistry of New Jersey (UMDNJ, USA) during 1999-2001, and was appointed as a principle investigator from 2001 and full professor from 2004, at Institute of Microbiology, Chinese Academy of Sciences. Dr. Xiang was awarded the National Science Fund for Distinguished Young Scholars by NSFC in 2009. He currently is the director of State Key Laboratory of Microbial Resources, and the director of the Committee of Microbial Genetics of the Genetics Society of China. He also served as associate editor of Journal of Genetics and Genomics, and editorial board member of Applied and Environmental Microbiology, Frontiers in Microbiology and Acta Microbiologica Sinica etc. The research interests of Dr. Xiang’s Lab are haloarchaeal genetics and metabolisms, current research projects include: 1) Genome replication mechanisms of archaea; 2) CRISPR-Cas system and genome editing; 3) Polyhydroxyalkanoates (bioplastics) biosynthesis by halophiles; and 4) Bioremediation in hypersaline environments.
Abstract: Autophagy is a highly conserved process for degrading cytoplasmic contents, determines cell survival or death, and regulates the cellular homeostasis. Besides core ATG proteins, numerous regulators together with various post-translational modifications (PTMs) are also involved in autophagy. Recent studies demonstrated that the dysregulation of macroautophagy/autophagy is involved in human diseases such as cancers and neurodegenerative disorders. Thus, autophagy has become a promising therapeutic target for biomedical design. Here, we developed a database of The Autophagy, Necrosis, ApopTosis OrchestratorS (THANATOS, http://thanatos.biocuckoo.org), containing 191,543 proteins potentially associated with autophagy and cell death pathways in 164 eukaryotes. We performed an evolutionary analysis of core ATG genes, and observed that ATGs required for the autophagosome formation are highly conserved across eukaryotes. Further analyses revealed that known cancer genes and drug targets were over-represented in human autophagy proteins, which were significantly associated in a number of signaling pathways and human diseases. By re-constructing a human kinase-substrate phosphorylation network for core ATG proteins, our results confirmed that phosphorylation play a critical role in regulating autophagy. Using this data resource, we performed a quantitative phosphoproteomic profiling to delineate the phosphorylation signalling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B). We developed a novel algorithm of in silico Kinome Activity Profiling (iKAP) to predict that Cory or Cory B potentially regulates different kinases. We discovered 2 kinases, MAP2K2/MEK2 (mitogen-activated protein kinase kinase 2) and PLK1 (polo-like kinase 1), to be potentially upregulated by Cory, whereas the siRNA-mediated knockdown of Map2k2 and Plk1 significantly inhibited Cory-induced autophagy. Furthermore, Cory promoted the clearance of Alzheimer disease-associated APP (amyloid beta [A4] precursor protein) and Parkinson disease-associated synuclein alpha (SNCA/α-synuclein) by enhancing autophagy, and these effects were dramatically diminished by the inhibition of the kinase activities of MAP2K2 and PLK1. Taken together, our study not only provided bioinformatics resources and approaches for analyzing PTMs in autophagy, but also identified the important role of MAP2K2 and PLK1 in neuronal autophagy.
Yu XUE Professor, Huazhong UST
Dr. Yu Xue is a professor at the Department of Biomedical Engineering of College of Life Science and Technology of Huazhong University of Science and Technology. He received his B.S. in Polymer Materials and Technology in 2002 and B.E. in Computer Science and Technology in 2003 from the University of Science and Technology of China (USTC). He completed his Ph.D. training in Cell Biology and Bioinformatics in USTC (2002-2006). After a short stage as a research assistant (2007.1-2007.7), he was recruited as an associate professor at the Department of Systems Biology of Life Science School of USTC (2007-2009). Dr. Xue has published extensively on computational studies of post-translational modifications (PTMs), including developing novel GPS (Group-based Prediction System) series algorithms, studying several new PTMs (eg., epigenetic modifications), constructing easy-to-use softwares and databases, and proteome-wide analysis of PTMs substrates, etc. His group is currently combining systems biology, bioinformatics, and molecular & cellular biology approaches to study genetic variations that potentially influence protein modification status. Dr. Xue is an academic Editor of PLoS ONE, and an associate Editor of BMC Genomics. He is also an active blogger for ScienceNet (In Chinese, http://blog.sciencenet.cn/u/DaCaiNiao) . He is quite active on pushing the communication and collaboration of young bioinformatists in China. Dr. Xue hope to resolve ALL computational problems for PTMs, but perhaps this aim might not be realized until his retirement. Thus, any collaborations, discussions and communications from all aspects including experimentalists and bioinformatists are warming welcome. The most favorable word for Dr. Xue is from Steven Wright, an American comedian and writer: "If you're not part of the solution, you're part of the precipitate".
Abstract: Eukaryotic pre-mRNAs undergo splicing to remove intragenic regions (introns) and ligate expressed regions (exons) together. Unlike exons in the mature mRNAs for translation, introns that are spliced out of pre-mRNAs were generally believed to lack function and to be degraded. However, recent studies have revealed that a large group of spliced introns can escape complete degradation and are processed to generate noncoding RNAs (ncRNAs), including different types of small RNAs, long noncoding RNAs and circular RNAs. Strikingly, exonic sequences can be also back-spliced from mRNA precursors to form stable circular RNAs (circRNAs)1. With the advent of specific biochemical and computational approaches, a large number of circRNAs have been identified in various cell lines and across different species1,2. Back-splicing requires canonical spliceosomal machinery and can be facilitated by both complementary sequences1, especially Alus in human, and specific protein factors that might bind to Alus3. Alu elements belong to the primate-specific SINE family of retrotransposons and constitute about 11% of the human genome. Recent advances on the mechanisms of circRNA biogenesis have revealed the multifaceted roles of Alus on circRNA formation and function coordinated with protein factors.
Li YANG Researcher, PICB, CAS
Abstract: Neural circuits underlying auditory fear conditioning have been extensively studied, with much attention on the amygdala. In this work, we identified a previously unexplored feedback projection from the lateral amygdala (LA) to the auditory cortex (ACx), and found that selective silencing of this pathway using chemogenetic (hM4d and CNO) and optogenetic (eArch3.0 and yellow light) approaches impairs fear memory retrieval. Long-term dual-color in vivo two-photon imaging showed a pathway-specific increase in the LA axon boutons, apical dendritic spines of ACx layer 5 neurons, and putative LA-ACx synaptic pairs after auditory fear conditioning. The synaptic remodeling of LA-ACx connections strongly correlated with fear responses, suggesting its involvement in fear memory. Interestingly, essentially all new synaptic contacts were made by newly formed boutons on existing spines or newly formed spines on existing boutons, indicating that new synapses are made by adding new partners to existing synaptic elements. Our findings unravel an important feedback projection which is selectively modified by associative fear learning, and suggest an architectural rule for synapse formation in the adult brain.
Yang YANG Assistant Professor, PI, ShanghaiTech University
Dr. Yang Yang graduated from Zhejiang University in 2005 majoring Biomedical engineering, and obtained her PhD degree in Neuroscience from Stony Brook University in 2010. She conducted her thesis work in Dr. Anthony M. Zador’s lab in Cold Spring Harbor Laboratory. She then joined Dr. Mu-ming Poo’s lab in 2011 as a postdoctoral fellow, and became Associate Investigator in 2015. She joined ShanghaiTech in June, 2017 as assistant professor and principle investigator.
Abstract: Aberrant DNA methylation is a critical feature in cancer development. Although there are ten hallmarks of cancer, but almost all malignant cancer accompany with two common feature of excessive proliferation and dedifferentiation. By analyzing global DNA methylation detection in tumor cell line and clinical Sample, we found Pan-tumor biomarker in clinical cancer sample and verified by Bisulfite pyrosequencing. We further apply them in the liquid biopsy for cancer diagnosis and therapy evaluation.
Wenqiang YU Professor, Fudan University
Chief-scientist of 973 project “Chromatin decode and its application in medical science”. Professor of “Chang Jiang scholars program”. PI of Institutes of Biomedical sciences of Fudan University. MD and PhD degree from the Fourth Military medical University. From 2001 to 2007 postdoc at Uppsala University and Johns Hopkins University Medical Center focus on epigenetics. From Nov 2007, faculty working in Columbia University as Associate Research Scientist studying on epigenetics and kidney development. Papers are published on Nature, Nature genetics, JAMA.
Abstract: Transplantation of embryonic γ-aminobutyric acid (GABA)ergic neurons has been shown to modify disease phenotypes in rodent models of neurologic and psychiatric disorders. However, whether transplanted interneurons modulate fear memory remains largely unclear. Here, we report that transplantation of embryonic interneurons into the amygdala does not alter host fear memory formation. Yet approximately 2 weeks after transplantation, but not earlier or later, extinction training produces a marked reduction in spontaneous recovery and renewal of fear response. Further analyses reveal that transplanted interneurons robustly form functional synapses with neurons of the host amygdala and exhibit similar developmental maturation in electrophysiological properties as native amygdala interneurons. Importantly, transplanted immature interneurons reduce the expression of perineuronal nets, promote long-term synaptic plasticity, and modulate both excitatory and inhibitory synaptic transmissions of the host circuits. Our findings demonstrate that transplanted immature interneurons modify amygdala circuitry and suggest a previously unknown strategy for the prevention of extinction-resistant pathological fear.
Yongchun YU Professor, Fudan University
Abstract: Many hemorheologic Traditional Chinese Medicines (TCMs) widely-used in clinic lack molecular mechanisms of action. We hypothesized that some of the active components of hemorheologic TCMs may function through targeting prothrombotic G protein-coupled receptors P2Y1 and/or P2Y12. The interactions between 253 antithrombotic compounds from TCM and the two P2Y receptors were evaluated by virtual screening. Eleven highly ranked predictions were further tested by radioligand binding and functional assays. Out of these eleven compounds, salvianolic acid A and C antagonized the activity of the P2Y1 and P2Y12 receptors in the low µM range, while salvianolic acid B antagonized the P2Y12 receptor. The three salvianolic acids are the major active components of the broadly-used hemorheologic TCM Danshen (Salvia militorrhiza), the antithrombotic molecular mechanism of which were largely unknown. Thus, the combination of virtual screening and experimental validation identified potential mechanisms of action of multicomponent drugs that are already employed clinically.
Suwen ZHAO Assistant Professor, PI, ShanghaiTech University
Predicting the full-length structures of multi-domain GPCRs
Discovering ligands for GPCRs and other proteins in cell signaling pathways
Abstract: Modifications on histone tails largely affect chromatin associated processes. Previous studies have shown the existence of asymmetrically modified nucleosomes in promoters in multiple cell types. However, whether modifications on both sister histones contribute equally to chromatin dynamics remains elusive. Here we devised a bivalent nucleosome system which allows for the constitutive assembly of asymmetrically modified sister histone H3 in nucleosomes in vivo. We found that the H3K36 methylation on either of sister histones sensitize chromatin structure in gene coding region, while the H3K79 methylation on both sister histone H3s are indispensable for maintaining silent chromatin near telomeres. Additionally, the H3K4 methylation on sister histones plays an equivalent role in suppressing the recruitment of Gal4 activator at GAL1 promoter and GAL1 transcription. Moreover, under starvation stress the expression of the genes in the glycometablism pathways is affected by the lack of the H3K4 methylation on one tail of the sister histones, indicating that both sister histones function in fine-tuning transcription through their modifications. We conclude that modifications on sister histones either cooperatively or independently respond to the change of an environmental cue to regulate chromatin structure and function. This work provides a unique experimental strategy to investigate the cross talk between sister histones, and for the first time elaborate their contributions to chromatin in vivo.
Jingqiu ZHOU Researcher, SIBCB, CAS
Abstract: The communication between cells and the communication between cellular organelles are often be controlled by the interaction of membrane proteins. Despite of many methods to detect protein-protein interactions (PPIs), there are still challenges in detecting membrane PPIs. Firstly, transient and weak PPIs are mostly associated with membrane receptor-mediated signaling pathways. Secondly, mass spectrometry-based membrane protein interaction studies have not been widely successful due to the poor solubility of membrane proteins or the loss of PPIs in sample preparation. Recent years, protein proximity tagging methods, such as APEX and BioID, have been applied in membrane protein study and showed great results.Here we developed another method, named PUP-IT, to specifically tag the interacting proteins of MPOI (membrane protein of interest) in cells. This approach can transform transient and weak interactions into covalent binding and the tagged proteins can be enriched by affinity purification under denaturing conditions for mass spectrometry-based identification. We applied this approach to CD28, a critical co-stimulatory receptor for T lymphocyte activation. Three known CD28 binding partners as well as multiple potential interacting proteins were identified. We also applied the PUP-IT approach to other membrane proteins and identified specific binders for each. In summary, we designed a powerful tool to uncover the weak and transient PPIs in cells, which will have a general application in discovering protein-protein interactions by mass spectrometry.
Min ZHUANG Assistant Professor, PI, ShanghaiTech University
Dr. Min Zhuang graduated from the Department for Intensive Instruction (current name: Kuang Yaming Honors School), Nanjing University in 2003. She completed the graduate training at St Jude Children’s Research Hospital and obtained her Ph.D. degree from The University of Tennessee Health Science Center in 2009. She continued her postdoctoral training in the Department of Pharmaceutical Chemistry at University of California San Francisco. In 2014, she joined ShanghaiTech University as a tenure-track assistant professor, PI in the School of Life Sciences and Technology.
Jie YIN Professor, Vice President & Provost, ShanghaiTech University
Prof. Jie Yin was a professor in Chemistry at Shanghai Jiao Tong University, and served as the Vice President of Shanghai Jiao Tong University for education programs from 2004 to 2009. Currently he is Vice President and Provost of ShanghaiTech University.
Ji-Long LIU Professor, Vice Dean, ShanghaiTech University
Professor Ji-Long Liu obtained a Bachelor degree from Beijing Forestry University in 1992, a Master degree from China Agricultural University in 1995 and a Ph.D. degree from Chinese Academy of Sciences Institute of Zoology in 2000. He was a postdoctoral fellow at the University of Connecticut from July 2000 to December 2002 and at Carnegie Institution for Science Department of Embryology from January 2003 to August 2007. He set up his laboratory and held a Medical Research Council (MRC) Programme Leader-track position at the University of Oxford in August 2007. He was promoted as a Tenured MRC Programme Leader at the University of Oxford in January 2012 (Tenured Programme Leader is the highest academic position in the UK MRC system). In June 2016, Professor Liu joined the School of Life Science and Technology at ShanghaiTech University as a Tenured Full Professor.Pro. Liu is appointed as Vice Dean in April 2017.
12 selected posters are pitched. 5 minutes for each
Poster Presenters Graduate/Postdoctoral/Undergraduate, Selected Posters
Presenter | Poster Number | Title
BASDORF, Pascal | P01 | Changed second messenger signaling in ongoing regeneration and effects in proliferation.
KUO, Shu-Ming | P30 | Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
Li, Na | P41 | A genetic screening to find suppressors that can allow C.elegans to survive without glucosylceramide
LIU, Yajing | P34 | Allele-specific genome editing based on DNA methylation by SaCas9
LU, Zongyang | P07 | Targeted DNA methylation of MeCP2 caused ASD-like syndrome
SUN, Zhe | P13 | mTORC1 controls CTP synthase polymerization
WANG, Lijie | P03 | Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor
ZHANG, Bo | P16 | Compartmentation of metabolic enzymes via coordinated filamentation
ZHANG, Jing | P11 | Systematic cancer genomic analysis identifies recurrent cancer driving CDC20 promoter mutation hotspots
ZHANG, Xianjun | P35 | Toward understanding the structural mechanism for Hedgehog signaling
ZHOU, Jianhong | P39 | Intrinsically disordered proteins link alternative splicing and post-translational modifications to complex cell signaling and regulation
ZHOU, Qingtong | P38 | In silico design of nucleic acid aptamer