Table of Contents
Aug 2017
Volume 27, Issue 8, Page 959-1074
About the Cover:  
  RESEARCH HIGHLIGHTS   ORIGINAL ARTICLES   EDITORIAL
  REVIEW   LETTER TO EDITOR   CORRIGENDA
  RESEARCH HIGHLIGHTS
Lingjuan He1 and Bin Zhou1,2
10.1038/cr.2017.91
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Adult mammalian hearts cannot repair by themselves after injury due to limited proliferation of cardiomyocytes; removal of cell cycle blocker and/or addition of drugs that boost proliferation of cardiomyocytes provide potential means to cardiac regeneration. Three publications that appeared recently in Nature and Cell Research now provide new hope to the treatment of heart injuries.
Caroline Kubaczka1,2,3 and George Q Daley1,2,3
10.1038/cr.2017.61
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Researchers at the University of Cambridge, UK have succeeded in reconstructing mouse embryos by combining pluripotent embryonic and multipotent trophoblast stem cells in a 3D scaffold; the study from the laboratory of Professor Zernicka-Goetz, recently published in Science, provides a break-through tool to probe early mammalian development outside the uterus. Achieving a similar feat with human cells might necessitate reconsideration of the 14-day rule as a limitation of such research.
Luca Cassetta1 and Jeffrey W Pollard1,2
10.1038/cr.2017.63
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Tumor-associated macrophages (TAMs) contribute to breast cancer progression and dissemination; TAM-targeting strategies aimed at their reprogramming show promising preclinical results. In a new report Guerriero and colleagues demonstrate that a novel HDAC Class IIa inhibitor, TMP195, can reprogram monocytes and macrophages in the tumor into cells able to sustain a robust CD8 T cell-mediated anti-tumoral immune response.
Bernadette Byrne1
10.1038/cr.2017.89
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Membrane transporter proteins are critical for cellular uptake and export of molecules, and are reported to function by a number of different molecular mechanisms. The new occluded state structure of the uracil transporter, UraA, from Escherichia coli, reveals that both coordinated movement of the two domains of a single protomer together with dimer formation are important for transport activity.
  ORIGINAL ARTICLES
Fan Guo1,2,3,4,*, Lin Li1,2,*, Jingyun Li1,2,3,5,*, Xinglong Wu1,2,5, Boqiang Hu1,2, Ping Zhu1,2,5, Lu Wen1,2 and Fuchou Tang1,2,3
10.1038/cr.2017.82
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Single-cell epigenome sequencing techniques have recently been developed. However, the combination of different layers of epigenome sequencing in an individual cell has not yet been achieved. Here, we developed a single-cell multi-omics sequencing technology (single-cell COOL-seq) that can analyze the chromatin state/nucleosome positioning, DNA methylation, copy number variation and ploidy simultaneously from the same individual mammalian cell. We used this method to analyze the reprogramming of the chromatin state and DNA methylation in mouse preimplantation embryos. We found that within < 12 h of fertilization, each individual cell undergoes global genome demethylation together with the rapid and global reprogramming of both maternal and paternal genomes to a highly opened chromatin state. This was followed by decreased openness after the late zygote stage. Furthermore, from the late zygote to the 4-cell stage, the residual DNA methylation is preferentially preserved on intergenic regions of the paternal alleles and intragenic regions of maternal alleles in each individual blastomere. However, chromatin accessibility is similar between paternal and maternal alleles in each individual cell from the late zygote to the blastocyst stage. The binding motifs of several pluripotency regulators are enriched at distal nucleosome depleted regions from as early as the 2-cell stage. This indicates that the cis-regulatory elements of such target genes have been primed to an open state from the 2-cell stage onward, long before pluripotency is eventually established in the ICM of the blastocyst. Genes may be classified into homogeneously open, homogeneously closed and divergent states based on the chromatin accessibility of their promoter regions among individual cells. This can be traced to step-wise transitions during preimplantation development. Our study offers the first single-cell and parental allele-specific analysis of the genome-scale chromatin state and DNA methylation dynamics at single-base resolution in early mouse embryos and provides new insights into the heterogeneous yet highly ordered features of epigenomic reprogramming during this process.
Meisheng Ma1,*, Jun-Jie Liu2,3,6,*, Yan Li2, Yuwei Huang1,3, Na Ta1, Yang Chen1, Hua Fu4, Ming-Da Ye2, Yuehe Ding5, Weijiao Huang2, Jia Wang2, Meng-Qiu Dong5, Li Yu1 and Hong-Wei Wang2
10.1038/cr.2017.94
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Phosphatidylinositol 3-phosphate (PI3P) plays essential roles in vesicular trafficking, organelle biogenesis and autophagy. Two class III phosphatidylinositol 3-kinase (PI3KC3) complexes have been identified in mammals, the ATG14L complex (PI3KC3-C1) and the UVRAG complex (PI3KC3-C2). PI3KC3-C1 is crucial for autophagosome biogenesis, and PI3KC3-C2 is involved in various membrane trafficking events. Here we report the cryo-EM structures of human PI3KC3-C1 and PI3KC3-C2 at sub-nanometer resolution. The two structures share a common L-shaped overall architecture with distinct features. EM examination revealed that PI3KC3-C1 “stands up” on lipid monolayers, with the ATG14L BATs domain and the VPS34 C-terminal domain (CTD) directly contacting the membrane. Biochemical dissection indicated that the ATG14L BATs domain is responsible for membrane anchoring, whereas the CTD of VPS34 determines the orientation. Furthermore, PI3KC3-C2 binds much more weakly than PI3KC3-C1 to both PI-containing liposomes and purified endoplasmic reticulum (ER) vesicles, a property that is specifically determined by the ATG14L BATs domain. The in vivo ER localization analysis indicated that the BATs domain was required for ER localization of PI3KC3. We propose that the different lipid binding capacity is the key factor that differentiates the functions of PI3KC3-C1 and PI3KC3-C2 in autophagy.
Ajit Magadum1,2,*, Yishu Ding3,*, Lan He3, Teayoun Kim3, Mohankrishna Dalvoy Vasudevarao4, Qinqiang Long3,5, Kevin Yang3, Nadeera Wickramasinghe6, Harsha V Renikunta1, Nicole Dubois6, Gilbert Weidinger4, Qinglin Yang3,5 and Felix B Engel1,7,8
10.1038/cr.2017.84
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Zebrafish can efficiently regenerate their heart through cardiomyocyte proliferation. In contrast, mammalian cardiomyocytes stop proliferating shortly after birth, limiting the regenerative capacity of the postnatal mammalian heart. Therefore, if the endogenous potential of postnatal cardiomyocyte proliferation could be enhanced, it could offer a promising future therapy for heart failure patients. Here, we set out to systematically identify small molecules triggering postnatal cardiomyocyte proliferation. By screening chemical compound libraries utilizing a Fucci-based system for assessing cell cycle stages, we identified carbacyclin as an inducer of postnatal cardiomyocyte proliferation. In vitro, carbacyclin induced proliferation of neonatal and adult mononuclear rat cardiomyocytes via a peroxisome proliferator-activated receptor δ (PPARδ)/PDK1/p308Akt/GSK3β/β-catenin pathway. Inhibition of PPARδ reduced cardiomyocyte proliferation during zebrafish heart regeneration. Notably, inducible cardiomyocyte-specific overexpression of constitutively active PPARδ as well as treatment with PPARδ agonist after myocardial infarction in mice induced cell cycle progression in cardiomyocytes, reduced scarring, and improved cardiac function. Collectively, we established a cardiomyocyte proliferation screening system and present a new drugable target with promise for the treatment of cardiac pathologies caused by cardiomyocyte loss.
Xinzhe Yu1,2,*, Guanghui Yang1,2,*, Chuangye Yan1,2, Javier L Baylon3, Jing Jiang1, He Fan1, Guifeng Lu1, Kazuya Hasegawa4, Hideo Okumura4, Tingliang Wang2, Emad Tajkhorshid3, Shuo Li5 and Nieng Yan1,2,3
10.1038/cr.2017.83
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The Escherichia coli uracil:proton symporter UraA is a prototypical member of the nucleobase/ascorbate transporter (NAT) or nucleobase/cation symporter 2 (NCS2) family, which corresponds to the human solute carrier family SLC23. UraA consists of 14 transmembrane segments (TMs) that are organized into two distinct domains, the core domain and the gate domain, a structural fold that is also shared by the SLC4 and SLC26 transporters. Here we present the crystal structure of UraA bound to uracil in an occluded state at 2.5 Å resolution. Structural comparison with the previously reported inward-open UraA reveals pronounced relative motions between the core domain and the gate domain as well as intra-domain rearrangement of the gate domain. The occluded UraA forms a dimer in the structure wherein the gate domains are sandwiched by two core domains. In vitro and in vivo biochemical characterizations show that UraA is at equilibrium between dimer and monomer in all tested detergent micelles, while dimer formation is necessary for the transport activity. Structural comparison between the dimeric UraA and the recently reported inward-facing dimeric UapA provides important insight into the transport mechanism of SLC23 transporters.
Young-hee Lee1,*, Natalia Martin-Orozco1,11,*, Peilin Zheng4,9,10, Jing Li7, Peng Zhang12, Haidong Tan13, Hyun Jung Park5, Mira Jeong6, Seon Hee Chang1, Byung-Seok Kim1, Wei Xiong9,10, Wenjuan Zang7, Li Guo14, Yang Liu12, Zhong-jun Dong7, Willem W Overwijk2, Patrick Hwu2, Qing Yi3,15, Larry Kwak3,16, Zhiying Yang13, Tak W Mak8, Wei Li5, Laszlo G Radvanyi2,11, Ling Ni7, Dongfang Liu4,9 and Chen Dong7
10.1038/cr.2017.90
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The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of B7-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8+ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.
Zhong Li1,*, Matthew Brecher1,*, Yong-Qiang Deng2,*, Jing Zhang1, Srilatha Sakamuru3, Binbin Liu1,4, Ruili Huang3, Cheri A Koetzner1, Christina A Allen5, Susan A Jones1, Haiying Chen6, Na-Na Zhang2, Min Tian2, Fengshan Gao1,7, Qishan Lin8, Nilesh Banavali1,9, Jia Zhou6, Nathan Boles5, Menghang Xia3, Laura D Kramer1,9, Cheng-Feng Qin2,10 and Hongmin Li1,9
10.1038/cr.2017.88
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Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics. The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.
  LETTERS TO THE EDITOR
Hui Ye1,3,*, Xiaobo Wang1,*, Zongcheng Li1, Fan Zhou1, Xianlong Li4, Yanli Ni1, Weijing Zhang5, Fuchou Tang3,6,7,8, Bing Liu1,2,9 and Yu Lan1,2
10.1038/cr.2017.64
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In conventional opinion, hematopoietic stem cells (HSCs) are alike, possessing robust self-renewal and multilineage differentiation capacity. However, growing evidence has revealed striking functional heterogeneity among individual HSCs, particularly in the aspect of lymphomyeloid output1,2,3. Four subtypes of HSCs with distinct differentiation patterns have been identified and designated as α-, β-, γ-, and δ-HSCs4.
Keliang Wu1,2,3,*, Cuiqing Zhong1,2,3,4,5,6,*, Tailai Chen1,2,3,*, Xiaoyu Zhang6, Wenrong Tao1,2,3, Jingye Zhang1,2,3, Hongchang Li1,2,3, Han Zhao1,2,3, Jinsong Li6,7 and Zi-Jiang Chen1,2,3,4,5
10.1038/cr.2017.67
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In mice, the first (1st) and second (2nd) polar bodies (PBs) can be used in place of the female genome of oocytes or zygotes and efficiently support the generation of embryonic stem cells (ESCs) and normal offspring1,2,3. These results indicate that both 1st and 2nd PBs can be used as nuclear donors for mitochondrial replacement therapy (MRT)4, which is an effective approach for preventing the transmission of disease-causing mutant mitochondria from mother to children5.
  CORRIGENDUM
Xiaoming Dai1,*, Huan Liu1,*, Shuying Shen1,2, Xiaocan Guo1, Huan Yan1, Xinyan Ji1, Li Li3, Jun Huang1, Xin-Hua Feng1 and Bin Zhao1
10.1038/cr.2017.96
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  RESEARCH HIGHLIGHTS
Bart Tummers1 and Douglas R Green1
10.1038/cr.2017.75
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Activation of the receptor interacting serine/threonine kinase (RIPK) 3 mediates an inflammatory type of cell death called necroptosis; in addition, RIPK3 has necroptosis-independent roles in inflammation, although these are not well defined. In a recent study published in Cell, Daniels and colleagues demonstrate that RIPK3 controls West Nile virus infection by promoting neuroinflammation in the central nervous system without affecting neuronal death.
 

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