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  • Pairing of integrins with ECM proteins determines migrasome formation
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Danni Wu, Yue Xu, Tianlun Ding, Yan Zu, Chun Yang, Li Yu1

    Recently we reported the discovery of migrasome, a new organelle of migrating cells1. Migrasomes are large vesicles that grow on the tips or intersections of retraction fibers at the rear of migrating cells. Following cell migration, the retraction fibers eventually break and the migrasomes become detached. The migrasomes and their contents, including cytosolic components and vesicles of unknown origin, are released into the extracellular space —— a process we named as migracytosis. We speculated that migracytosis may play important roles in cell-cell communication.

    更新日期:2017-11-06
  • An essential role for PNLDC1 in piRNA 3′ end trimming and male fertility in mice
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Yue Zhang, Rui Guo, Yiqiang Cui, Zhiping Zhu, Yingwen Zhang, Hao Wu, Bo Zheng, Qiuling Yue, Shun Bai, Wentao Zeng, Xuejiang Guo, Zuomin Zhou, Bin Shen, Ke Zheng, Mingxi Liu, Lan Ye, Jiahao Sha

    PIWI-interacting RNAs (piRNAs) are germ cell-specific small non-coding RNAs that are essential for silencing transposable elements. Substantial efforts in the past decade have led to an understanding of how piRNAs are made. Primary piRNA biogenesis is initiated with transcription of piRNA precursors, followed by cleavage into piRNA intermediates, and finally, maturation by 3′ end trimming and 2′-O-methylation. Secondary piRNA biogenesis occurs through an amplification loop (ping pong pathway); the piRNA pools generated through primary processing guide MILI protein to cleave the target RNA for piRNA generation in a feed-forward loop that accelerates production of the piRNAs. Papi/Tdrkh has been implicated in processing the 3′ ends of piRNAs1,2, however, Papi/Tdrkh lacks a recognized domain for nuclease activity. Recently, two independent studies identified the proteins that function as piRNA 3′ end trimmers in silkworms-the poly(A) specific ribonuclease PARN-1 and the PARN-like ortholog PNLDC13,4.

    更新日期:2017-11-06
  • Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Sixue Ren, Antonella Caforio, Qin Yang, Bo Sun, Feng Yu, Xiaofeng Zhu, Jinjing Wang, Chao Dou, Qiuyu Fu, Niu Huang, Qiu Sun, Chunlai Nie, Shiqian Qi, Xinqi Gong, Jianhua He, Yuquan Wei, Arnold JM Driessen, Wei Cheng

    The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg2+-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg2+ enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.

    更新日期:2017-11-06
  • Molecular mechanism of directional CTCF recognition of a diverse range of genomic sites
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Maolu Yin, Jiuyu Wang, Min Wang, Xinmei Li, Mo Zhang, Qiang Wu, Yanli Wang

    CTCF, a conserved 3D genome architecture protein, determines proper genome-wide chromatin looping interactions through directional binding to specific sequence elements of four modules within numerous CTCF-binding sites (CBSs) by its 11 zinc fingers (ZFs). Here, we report four crystal structures of human CTCF in complex with CBSs of the protocadherin (Pcdh) clusters. We show that directional CTCF binding to cognate CBSs of the Pcdh enhancers and promoters is achieved through inserting its ZF3, ZFs 4-7, and ZFs 9-11 into the major groove along CBSs, resulting in a sequence-specific recognition of module 4, modules 3 and 2, and module 1, respectively; and ZF8 serves as a spacer element for variable distances between modules 1 and 2. In addition, the base contact with the asymmetric “A” in the central position of modules 2-3, is essential for directional recognition of the CBSs with symmetric core sequences but lacking module 1. Furthermore, CTCF tolerates base changes at specific positions within the degenerated CBS sequences, permitting genome-wide CTCF binding to a diverse range of CBSs. Together, these complex structures provide important insights into the molecular mechanisms for the directionality, diversity, flexibility, dynamics, and conservation of multivalent CTCF binding to its cognate sites across the entire human genome.

    更新日期:2017-11-06
  • A vital sugar code for ricin toxicity
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Jasmin Taubenschmid, Johannes Stadlmann, Markus Jost, Tove Irene Klokk, Cory D Rillahan, Andreas Leibbrandt, Karl Mechtler, James C Paulson, Julian Jude, Johannes Zuber, Kirsten Sandvig, Ulrich Elling, Thorsten Marquardt, Christian Thiel, Christian Koerner, Josef M Penninger

    Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.

    更新日期:2017-11-06
  • Cryo-EM structure of human DNA-PK holoenzyme
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Xiaotong Yin, Mengjie Liu, Yuan Tian, Jiawei Wang, Yanhui Xu

    DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 Å resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal α-solenoid (~2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA. DNA-PKcs and KU70/80 together form a DNA-binding tunnel, which cradles ~30-bp DNA and prevents sliding inward of DNA-PKcs along with DNA duplex, suggesting a mechanism by which the broken DNA end is protected from unnecessary processing. Structural and biochemical analyses indicate that KU70/80 and DNA coordinately induce conformational changes of DNA-PKcs and allosterically stimulate its kinase activity. We propose a model for activation of DNA-PKcs in which allosteric signals are generated upon DNA-PK holoenzyme formation and transmitted to the kinase domain through N-terminal HEAT repeats and FAT domain of DNA-PKcs. Our studies suggest a mechanism for recognition and protection of broken DNA ends and provide a structural basis for understanding the activation of DNA-PKcs and DNA-PK-mediated NHEJ pathway.

    更新日期:2017-11-06
  • A high-quality genome assembly of quinoa provides insights into the molecular basis of salt bladder-based salinity tolerance and the exceptional nutritional value
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Changsong Zou, Aojun Chen, Lihong Xiao, Heike M Muller, Peter Ache, Georg Haberer, Meiling Zhang, Wei Jia, Ping Deng, Ru Huang, Daniel Lang, Feng Li, Dongliang Zhan, Xiangyun Wu, Hui Zhang, Jennifer Bohm, Renyi Liu, Sergey Shabala, Rainer Hedrich, Jian-Kang Zhu, Heng Zhang

    Chenopodium quinoa is a halophytic pseudocereal crop that is being cultivated in an ever-growing number of countries. Because quinoa is highly resistant to multiple abiotic stresses and its seed has a better nutritional value than any other major cereals, it is regarded as a future crop to ensure global food security. We generated a high-quality genome draft using an inbred line of the quinoa cultivar Real. The quinoa genome experienced one recent genome duplication about 4.3 million years ago, likely reflecting the genome fusion of two Chenopodium parents, in addition to the γ paleohexaploidization reported for most eudicots. The genome is highly repetitive (64.5% repeat content) and contains 54 438 protein-coding genes and 192 microRNA genes, with more than 99.3% having orthologous genes from glycophylic species. Stress tolerance in quinoa is associated with the expansion of genes involved in ion and nutrient transport, ABA homeostasis and signaling, and enhanced basal-level ABA responses. Epidermal salt bladder cells exhibit similar characteristics as trichomes, with a significantly higher expression of genes related to energy import and ABA biosynthesis compared with the leaf lamina. The quinoa genome sequence provides insights into its exceptional nutritional value and the evolution of halophytes, enabling the identification of genes involved in salinity tolerance, and providing the basis for molecular breeding in quinoa.

    更新日期:2017-11-06
  • Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Kyoung-Han Kim, Yun Hye Kim, Joe Eun Son, Ju Hee Lee, Sarah Kim, Min Seon Choe, Joon Ho Moon, Jian Zhong, Kiya Fu, Florine Lenglin, Jeong-Ah Yoo, Philip J Bilan, Amira Klip, Andras Nagy, Jae-Ryong Kim, Jin Gyoon Park, Samer MI Hussein, Kyung-Oh Doh, Chi-chung Hui, Hoon-Ki Sung

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

    更新日期:2017-11-06
  • tsRNAs: new players in mammalian retrotransposon control
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Yunfang Zhang, Junchao Shi, Qi Chen

    A recent study led by Professor Rob Martienssen in Cell showed that 3′-tRNA-derived small RNAs can suppress long terminal repeat retrotransposon activity in mammalian cells by mechanisms independent of DNA-associated epigenetic marks, suggesting how the genome may defend itself from retrotransposon invasion during epigenetic reprogramming.

    更新日期:2017-11-06
  • Structural step forward for NHEJ
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Go Watanabe, Michael R Lieber, Dewight Williams

    In a recent paper published in Cell Research, a cryo-EM structure reveals the interface between DNA-PKcs and the Ku70/80:DNA complex, together forming the DNA-dependent protein kinase holoenzyme in non-homologous DNA end joining. Insight from this structure suggests how an allosteric rearrangement of DNA-PKcs driven by Ku70/80:DNA binding regulates kinase activity in this largest member of a family of structurally homologous phosphoinositide 3-kinase-related protein kinases that includes mTOR, ATR, and ATM.

    更新日期:2017-11-06
  • NLRP9b: a novel RNA-sensing inflammasome complex
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Chinh Ngo, Si Ming Man

    Inflammasome sensors recognize pathogens and danger signals and assemble an immune signaling complex, which induces the secretion of pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. A new study published in Nature now describes a new inflammasome sensor NLRP9b in intestinal epithelial cells, which in concert with the RNA sensor DHX9, recognize short dsRNA from Rotavirus.

    更新日期:2017-11-06
  • White adipose tissue coloring by intermittent fasting
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Riikka Kivelä, Kari Alitalo

    Intermittent fasting (IF) has been shown to promote metabolic health in several organisms. Two recent papers show that IF induces white adipose tissue beiging and increases thermogenesis, which improves metabolic health in mice.

    更新日期:2017-11-06
  • Sanofi-Cell Research outstanding paper award of 2016
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Editorial Office

    None

    更新日期:2017-11-06
  • Human embryonic stem cells contribute to embryonic and extraembryonic lineages in mouse embryos upon inhibition of apoptosis
    Cell Res. (IF 15.606) Pub Date : 2017-11-03
    Xuepeng Wang, Tianda Li, Tongtong Cui, Dawei Yu, Chao Liu, Liyuan Jiang, Guihai Feng, Lei Wang, Rui Fu, Xinxin Zhang, Jie Hao, Yukai Wang, Liu Wang, Qi Zhou, Wei Li, Baoyang Hu

    Recently, interspecies chimera formation has been established in rodents by injection of rat pluripotent stem cells (PSCs) into mouse early embryos, and such a system provides an in vivo assay to test the developmental potential of human PSCs (hPSCs)1. In addition, the interspecies chimeras formed between hPSCs and large animal embryos would open new avenues to generate human tissues and organs for regenerative medicine2. In rodents, embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) have been derived from inner cell mass (ICM) of the blastocyst and post-implantation epiblast respectively3,4. Although both being pluripotent, the ESCs and EpiSCs are considered to represent two distinct states of pluripotency, the naïve and primed pluripotent state. Only naïve state ESCs can colonize the early embryos before the blastocyst stage to form adult chimeras and transmit to the germline, while the primed state EpiSCs can only integrate into the post-implantation embryos5,6. Intriguingly, although derived from the ICM, the human ESCs (hESCs) are similar to the mouse EpiSCs in many aspects such as the morphology and self-renewal pathways, hence they are considered to represent the primed pluripotent state. Several studies have reported the generation of human-animal interspecies chimeras using the stage-matching hESCs. For example, primed hPSCs were engrafted into in vitro cultured gastrula-stage mouse embryos to form chimeras, and the primed hPSCs were also converted into a naïve-like state and then were injected into pre-implantation embryos to form mouse or pig chimeras7,8,9.

    更新日期:2017-11-06
  • Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage
    Cell Res. (IF 15.606) Pub Date : 2017-10-17
    Kyoung-Han Kim, Yun Hye Kim, Joe Eun Son, Ju Hee Lee, Sarah Kim, Min Seon Choe, Joon Ho Moon, Jian Zhong, Kiya Fu, Florine Lenglin, Jeong-Ah Yoo, Philip J Bilan, Amira Klip, Andras Nagy, Jae-Ryong Kim, Jin Gyoon Park, Samer MI Hussein, Kyung-Oh Doh, Chi-chung Hui, Hoon-Ki Sung

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

    更新日期:2017-10-18
  • Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3-deficient non-human primate
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Hui Zhao, Zhuchi Tu, Huijuan Xu, Sen Yan, Huanhuan Yan, Yinghui Zheng, Weili Yang, Jiezhao Zheng, Zhujun Li, Rui Tian, Youming Lu, Xiangyu Guo, Yong-hui Jiang, Xiao-Jiang Li, Yong Q Zhang

    Despite substantial progress made toward understanding the molecular changes contributing to autism spectrum disorders (ASD), the neuropathophysiology underlying ASD remains poorly understood1,2. Structural brain imaging in humans is valuable, but lacks resolution at the cellular level. Studies of neuropathology in humans have been hampered by the lack of high quality postmortem brains from individuals with ASD2. For more than decades, mutant mice have served as major tools to dissect the pathophysiology of ASD because of the wealth of molecular and neurobiological techniques developed for studies with rodents. Our knowledge of molecular and cellular mechanisms for ASD is mostly limited to what we have learned from genetically modified mice. However, there are significant evolutionary differences in brain structure and behavior between rodents and humans. For example, social behaviors and the organization of cerebral cortex differ significantly between primates and rodents. The cerebral neocortex comprises ~80% of the human brain and ~72% of the macaque brain, but only ~28% of the rat brain. Prefrontal cortex (PFC), a critical region for high order cognitive and social functions, is under-developed in rodents compared with primates. The unique behavioral features in human ASD have posed significant challenges to assess the translational value of many findings from ASD mouse models. The apparent evolutionary differences in brain structures and behaviors between mouse and human highlight the need of alternative animal models such as non-human primate models for ASD3.

    更新日期:2017-10-18
  • Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Lijie Wang, Wei Xue, Lei Yan, Xiaosa Li, Jia Wei, Miaomiao Chen, Jing Wu, Bei Yang, Li Yang, Jia Chen

    Base editors (BEs) have been recently developed by combining the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)/AID (activation-induced deaminase) cytidine deaminase family members1 with the CRISPR/Cas9 system to perform targeted C-to-T base editing2, 3, 4, 5,6,7,8. Mechanistically, Cas9 variant-fused APOBEC/AID is directed to target site by sgRNA, introducing C-to-T substitution at the single-base level2,3,4. Compared to earlier generations of BEs (BE1 and BE2), the latest BE3 achieved much higher base editing frequencies by substituting catalytically-dead Cas9 (dCas9) with Cas9 nickase (nCas9)2.

    更新日期:2017-10-18
  • Cryo-EM structures of the 80S ribosomes from human parasites Trichomonas vaginalis and Toxoplasma gondii
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Zhifei Li, Qiang Guo, Lvqin Zheng, Yongsheng Ji, Yi-Ting Xie, De-Hua Lai, Zhao-Rong Lun, Xun Suo, Ning Gao

    As an indispensable molecular machine universal in all living organisms, the ribosome has been selected by evolution to be the natural target of many antibiotics and small-molecule inhibitors. High-resolution structures of pathogen ribosomes are crucial for understanding the general and unique aspects of translation control in disease-causing microbes. With cryo-electron microscopy technique, we have determined structures of the cytosolic ribosomes from two human parasites, Trichomonas vaginalis and Toxoplasma gondii, at resolution of 3.2–3.4 Å. Although the ribosomal proteins from both pathogens are typical members of eukaryotic families, with a co-evolution pattern between certain species-specific insertions/extensions and neighboring ribosomal RNA (rRNA) expansion segments, the sizes of their rRNAs are sharply different. Very interestingly, rRNAs of T. vaginalis are in size comparable to prokaryotic counterparts, with nearly all the eukaryote-specific rRNA expansion segments missing. These structures facilitate the dissection of evolution path for ribosomal proteins and RNAs, and may aid in design of novel translation inhibitors.

    更新日期:2017-10-18
  • Genome-wide identification of histone H2A and histone variant H2A.Z-interacting proteins by bPPI-seq
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Yi Zhang, Wai Lim Ku, Shuai Liu, Kairong Cui, Wenfei Jin, Qingsong Tang, William Lu, Bing Ni, Keji Zhao

    H2A is a nucleosome core subunit involved in organizing DNA into a chromatin structure that is often inaccessible to regulatory enzymes. Replacement of H2A by its variant H2A.Z renders chromatin accessible at enhancers and promoters. However, it remains unclear how H2A.Z functions so differently from canonical H2A. Here we report the genome-wide identification of proteins that directly interact with H2A and H2A.Z in vivo using a novel strategy, bPPI-seq. We show that bPPI-seq is a sensitive and robust technique to identify protein-protein interactions in vivo. Our data indicate that H2A.Z-interacting proteins and H2A-interacting proteins participate in distinct biological processes. In contrast to H2A-interacting proteins, the H2A.Z-interacting proteins are involved in transcriptional regulation. We found that the transcription factor Osr1 interacts with H2A.Z both in vitro and in vivo. It also mediates H2A.Z incorporation to a large number of target sites and regulates gene expression. Our data indicate that bPPI-seq can be widely applied to identify genome-wide interacting proteins under physiological conditions.

    更新日期:2017-10-18
  • 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Wenshuai Li, Xu Zhang, Xingyu Lu, Lei You, Yanqun Song, Zhongguang Luo, Jun Zhang, Ji Nie, Wanwei Zheng, Diannan Xu, Yaping Wang, Yuanqiang Dong, Shulin Yu, Jun Hong, Jianping Shi, Hankun Hao, Fen Luo, Luchun Hua, Peng Wang, Xiaoping Qian, Fang Yuan, Lianhuan Wei, Ming Cui, Taiping Zhang, Quan Liao, Menghua Dai, Ziwen Liu, Ge Chen, Katherine Meckel, Sarbani Adhikari, Guifang Jia, Marc B Bissonnette, Xinxiang Zhang, Yupei Zhao, Wei Zhang, Chuan He, Jie Liu

    DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

    更新日期:2017-10-18
  • 5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Chun-Xiao Song, Senlin Yin, Li Ma, Amanda Wheeler, Yu Chen, Yan Zhang, Bin Liu, Junjie Xiong, Weihan Zhang, Jiankun Hu, Zongguang Zhou, Biao Dong, Zhiqi Tian, Stefanie S Jeffrey, Mei-Sze Chua, Samuel So, Weimin Li, Yuquan Wei, Jiajie Diao, Dan Xie, Stephen R Quake

    5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.

    更新日期:2017-10-18
  • Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Zhen Lin, Phillip J Hsu, Xudong Xing, Jianhuo Fang, Zhike Lu, Qin Zou, Ke-Jia Zhang, Xiao Zhang, Yuchuan Zhou, Teng Zhang, Youcheng Zhang, Wanlu Song, Guifang Jia, Xuerui Yang, Chuan He, Ming-Han Tong

    Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine (m6A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m6A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

    更新日期:2017-10-18
  • Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Mohammad Abdul-Ghani, Colin Suen, Baohua Jiang, Yupu Deng, Jonathan J Weldrick, Charis Putinski, Steve Brunette, Pasan Fernando, Tom T Lee, Peter Flynn, Frans H H Leenen, Patrick G Burgon, Duncan J Stewart, Lynn A Megeney

    The post-natal heart adapts to stress and overload through hypertrophic growth, a process that may be pathologic or beneficial (physiologic hypertrophy). Physiologic hypertrophy improves cardiac performance in both healthy and diseased individuals, yet the mechanisms that propagate this favorable adaptation remain poorly defined. We identify the cytokine cardiotrophin 1 (CT1) as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity. The capacity of CT1 to induce physiologic hypertrophy originates from a CK2-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth. Exogenous CT1 protein delivery attenuated pathology and restored contractile function in a severe model of right heart failure, suggesting a novel treatment option for this intractable cardiac disease.

    更新日期:2017-10-18
  • Coding GPCR-G protein specificity
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Sebastian GB Furness, Patrick M Sexton

    G protein-coupled receptors (GPCRs) are ubiquitous gatekeepers of cellular response and signal predominantly by recruitment and activation of G proteins. In a recent paper in Nature, Flock et al. use large-scale bioinformatics to build a model of GPCR-G protein selectivity and an interactive database to interrogate potential receptor-G protein interactions.

    更新日期:2017-10-18
  • IPA1: a direct target of SL signaling
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Stephanie C Kerr, Christine A Beveridge

    The plant hormone strigolactone (SL) is important for many processes in plants, but its molecular mode of action has been difficult to elucidate. A new discovery has identified the SPL transcription factor, IPA1, as a crucial component directly involved in SL signaling.

    更新日期:2017-10-18
  • New path towards a better rice architecture
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Reynante L Ordonio, Makoto Matsuoka

    New plant type (NPT) or ideal plant architecture (IPA) is an attractive way of increasing yield potential by promoting high resource use efficiency combined with better lodging resistance. In a recent paper in Cell Research, Wang et al. describe how a QTL they identified could bring about the desired NPT architecture by elucidating the role of its encoded gene in controlling the stability of IPA1/OsSPL14, a previously reported NPT protein, in the context of ubiquitination.

    更新日期:2017-10-18
  • Size matters: Finding growth pathways that protect the heart
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    J Sawalla Guseh, Anthony Rosenzweig

    In a recent paper published in Cell Research, Abdul-Ghani and colleagues show that the cytokine, cardiotrophin-1 (CT1), drives a protective form of reversible cardiac hypertrophy that acts through a nonapoptotic caspase-dependent mechanism. Since CT1 can be delivered as exogenous protein, these studies provide new biological insights and potential translational opportunities.

    更新日期:2017-10-18
  • Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes
    Cell Res. (IF 15.606) Pub Date : 2017-09-29
    Sixue Ren, Antonella Caforio, Qin Yang, Bo Sun, Feng Yu, Xiaofeng Zhu, Jinjing Wang, Chao Dou, Qiuyu Fu, Niu Huang, Qiu Sun, Chunlai Nie, Shiqian Qi, Xinqi Gong, Jianhua He, Yuquan Wei, Arnold JM Driessen, Wei Cheng

    The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg2+-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg2+ enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.

    更新日期:2017-10-10
  • Structural basis for BIR1-mediated negative regulation of plant immunity
    Cell Res. (IF 15.606) Pub Date : 2017-09-29
    Cuiyan Ma, Yanan Liu, Bing Bai, Zhifu Han, Jiao Tang, Heqiao Zhang, Hoda Yaghmaiean, Yuelin Zhang, Jijie Chai

    Plant receptor kinases (RKs) can function as pattern recognition receptors (PRRs) for perception of pathogen-associated molecular patterns (PAMPs) to induce immune responses1,2. One of such PRRs is the leucine-rich repeat RK (LRR-RK) FLAGELLIN-SENSING 2 (FLS2) that recognizes bacteria-derived flagellin (flg22 epitope)3,4. The smaller LRR-RK BRI1-associated kinase 1 (BAK1) acts as a co-receptor with FLS25,6.

    更新日期:2017-10-10
  • Structural step forward for NHEJ
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Go Watanabe, Michael R Lieber, Dewight Williams

    In a recent paper published in Cell Research, a cryo-EM structure reveals the interface between DNA-PKcs and the Ku70/80:DNA complex, together forming the DNA-dependent protein kinase holoenzyme in non-homologous DNA end joining. Insight from this structure suggests how an allosteric rearrangement of DNA-PKcs driven by Ku70/80:DNA binding regulates kinase activity in this largest member of a family of structurally homologous phosphoinositide 3-kinase-related protein kinases that includes mTOR, ATR, and ATM.

    更新日期:2017-09-22
  • Fine-tuning type I IFN signaling: A new chapter in the IFN saga
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Hideyuki Yanai, Tadatsugu Taniguchi

    Type I interferon (IFN) signaling is critical for intracellular antimicrobial programmes, affecting both innate and adaptive immune responses. The paper recently published in Cell demonstrates a new regulatory mechanism of the type I IFN signaling pathway by histone-lysine N-methyltransferase SETD2.

    更新日期:2017-09-22
  • 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Wenshuai Li, Xu Zhang, Xingyu Lu, Lei You, Yanqun Song, Zhongguang Luo, Jun Zhang, Ji Nie, Wanwei Zheng, Diannan Xu, Yaping Wang, Yuanqiang Dong, Shulin Yu, Jun Hong, Jianping Shi, Hankun Hao, Fen Luo, Luchun Hua, Peng Wang, Xiaoping Qian, Fang Yuan, Lianhuan Wei, Ming Cui, Taiping Zhang, Quan Liao, Menghua Dai, Ziwen Liu, Ge Chen, Katherine Meckel, Sarbani Adhikari, Guifang Jia, Marc B Bissonnette, Xinxiang Zhang, Yupei Zhao, Wei Zhang, Chuan He, Jie Liu

    DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

    更新日期:2017-09-22
  • Size matters: Finding growth pathways that protect the heart
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    J Sawalla Guseh, Anthony Rosenzweig

    In a recent paper published in Cell Research, Abdul-Ghani and colleagues show that the cytokine, cardiotrophin-1 (CT1), drives a protective form of reversible cardiac hypertrophy that acts through a nonapoptotic caspase-dependent mechanism. Since CT1 can be delivered as exogenous protein, these studies provide new biological insights and potential translational opportunities.

    更新日期:2017-09-22
  • A vital sugar code for ricin toxicity
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Jasmin Taubenschmid, Johannes Stadlmann, Markus Jost, Tove Irene Klokk, Cory D Rillahan, Andreas Leibbrandt, Karl Mechtler, James C Paulson, Julian Jude, Johannes Zuber, Kirsten Sandvig, Ulrich Elling, Thorsten Marquardt, Christian Thiel, Christian Koerner, Josef M Penninger

    Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.

    更新日期:2017-09-22
  • New path towards a better rice architecture
    Cell Res. (IF 15.606) Pub Date : 2017-09-12
    Reynante L Ordonio, Makoto Matsuoka

    New plant type (NPT) or ideal plant architecture (IPA) is an attractive way of increasing yield potential by promoting high resource use efficiency combined with better lodging resistance. In a recent paper in Cell Research, Wang et al. describe how a QTL they identified could bring about the desired NPT architecture by elucidating the role of its encoded gene in controlling the stability of IPA1/OsSPL14, a previously reported NPT protein, in the context of ubiquitination.

    更新日期:2017-09-15
  • Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor
    Cell Res. (IF 15.606) Pub Date : 2017-08-29
    Lijie Wang, Wei Xue, Lei Yan, Xiaosa Li, Jia Wei, Miaomiao Chen, Jing Wu, Bei Yang, Li Yang, Jia Chen

    Base editors (BEs) have been recently developed by combining the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)/AID (activation-induced deaminase) cytidine deaminase family members1 with the CRISPR/Cas9 system to perform targeted C-to-T base editing2, 3, 4, 5,6,7,8. Mechanistically, Cas9 variant-fused APOBEC/AID is directed to target site by sgRNA, introducing C-to-T substitution at the single-base level2,3,4. Compared to earlier generations of BEs (BE1 and BE2), the latest BE3 achieved much higher base editing frequencies by substituting catalytically-dead Cas9 (dCas9) with Cas9 nickase (nCas9)2.

    更新日期:2017-08-31
  • RIPped for neuroinflammation
    Cell Res. (IF 15.606) Pub Date : 2017-08-24
    Bart Tummers, Douglas R Green

    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.

    更新日期:2017-08-25
  • YAP activates the Hippo pathway in a negative feedback loop
    Cell Res. (IF 15.606) Pub Date : 2017-08-24
    Xiaoming Dai, Huan Liu, Shuying Shen, Xiaocan Guo, Huan Yan, Xinyan Ji, Li Li, Jun Huang, Xin-Hua Feng, Bin Zhao

    10.1038/cr.2017.96

    更新日期:2017-08-25
  • Fibroblasts in an endocardial fibroelastosis disease model mainly originate from mesenchymal derivatives of epicardium
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Hui Zhang, Xiuzhen Huang, Kuo Liu, Juan Tang, Lingjuan He, Wenjuan Pu, Qiaozhen Liu1,2, Yan Li, Xueying Tian, Yue Wang, Libo Zhang, Ying Yu, Hongyan Wang, Ronggui Hu, Fengchao Wang, Ting Chen, Qing-Dong Wang, Zengyong Qiao, Li Zhang, Kathy O Lui8 and Bin Zhou

    Endocardial fibroelastosis (EFE) refers to the thickening of the ventricular endocardium as a result of de novo deposition of subendocardial fibrous tissue layers during neonatal heart development. The origin of EFE fibroblasts is proposed to be postnatal endocardial cells that undergo an aberrant endothelial-to-mesenchymal transition (EndMT). Genetic lineage tracing of endocardial cells with the inducible endocardial Cre line Npr3-CreER and the endothelial cell tracing line Cdh5-CreER on an EFE-like model did not reveal any contribution of neonatal endocardial cells to fibroblasts in the EFE-like tissues. Instead, lineage tracing of embryonic epicardium by Wt1-CreER suggested that epicardium-derived mesenchymal cells (MCs) served as the major source of EFE fibroblasts. By labeling MCs using Sox9-CreER, we confirmed that MCs of the embryonic heart expand and contribute to the majority of neonatal EFE fibroblasts. During this pathological process, TGFβ signaling, the key mediator of fibroblasts activation, was highly upregulated in the EFE-like tissues. Targeting TGFβ signaling by administration of its antagonist bone morphogenetic protein 7 effectively reduced fibroblast accumulation and tissue fibrosis in the EFE-like model. Our study provides genetic evidence that excessive fibroblasts in the EFE-like tissues mainly originate from the epicardium-derived MCs through epicardial to mesenchymal transition (EpiMT). These EpiMT-derived fibroblasts within the EFE-like tissues could serve as a potential therapeutic target.

    更新日期:2017-08-18
  • Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Kai Xu, Ying Yang, Gui-Hai Feng, Bao-Fa Sun, Jun-Qing Chen, Yu-Fei Li, Yu-Sheng Chen, Xin-Xin Zhang, Chen-Xin Wang, Li-Yuan Jiang, Chao Liu, Ze-Yu Zhang, Xiu-Jie Wang, Qi Zhou, Yun-Gui Yang, Wei Li

    METTL3 catalyzes the formation of N6-methyl-adenosine (m6A) which has important roles in regulating various biological processes. However, the in vivo function of Mettl3 remains largely unknown in mammals. Here we generated germ cell-specific Mettl3 knockout mice and demonstrated that Mettl3 was essential for male fertility and spermatogenesis. The ablation of Mettl3 in germ cells severely inhibited spermatogonial differentiation and blocked the initiation of meiosis. Transcriptome and m6A profiling analysis revealed that genes functioning in spermatogenesis had altered profiles of expression and alternative splicing. Our findings provide novel insights into the function and regulatory mechanisms of Mettl3-mediated m6A modification in spermatogenesis and reproduction in mammals.

    更新日期:2017-08-18
  • IPA1 functions as a downstream transcription factor repressed by D53 in strigolactone signaling in rice
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Xiaoguang Song, Zefu Lu, Hong Yu, Gaoneng Shao, Jinsong Xiong, Xiangbing Meng, Yanhui Jing, Guifu Liu, Guosheng Xiong, Jingbo Duan, Xue-Feng Yao, Chun-Ming Liu, Hongqing Li, Yonghong Wang, Jiayang Li

    Strigolactones (SLs), a group of carotenoid derived terpenoid lactones, are root-to-shoot phytohormones suppressing shoot branching by inhibiting the outgrowth of axillary buds. DWARF 53 (D53), the key repressor of the SL signaling pathway, is speculated to regulate the downstream transcriptional network of the SL response. However, no downstream transcription factor targeted by D53 has yet been reported. Here we report that Ideal Plant Architecture 1 (IPA1), a key regulator of the plant architecture in rice, functions as a direct downstream component of D53 in regulating tiller number and SL-induced gene expression. We showed that D53 interacts with IPA1 in vivo and in vitro and suppresses the transcriptional activation activity of IPA1. We further showed that IPA1 could directly bind to the D53 promoter and plays a critical role in the feedback regulation of SL-induced D53 expression. These findings reveal that IPA1 is likely one of the long-speculated transcription factors that act with D53 to mediate the SL-regulated tiller development in rice.

    更新日期:2017-08-18
  • Cryo-EM structures of the 80S ribosomes from human parasites Trichomonas vaginalis and Toxoplasma gondii
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Zhifei Li, Qiang Guo, Lvqin Zheng, Yongsheng Ji, Yi-Ting Xie, De-Hua Lai, Zhao-Rong Lun, Xun Suo, Ning Gao

    As an indispensable molecular machine universal in all living organisms, the ribosome has been selected by evolution to be the natural target of many antibiotics and small-molecule inhibitors. High-resolution structures of pathogen ribosomes are crucial for understanding the general and unique aspects of translation control in disease-causing microbes. With cryo-electron microscopy technique, we have determined structures of the cytosolic ribosomes from two human parasites, Trichomonas vaginalis and Toxoplasma gondii, at resolution of 3.2–3.4 Å. Although the ribosomal proteins from both pathogens are typical members of eukaryotic families, with a co-evolution pattern between certain species-specific insertions/extensions and neighboring ribosomal RNA (rRNA) expansion segments, the sizes of their rRNAs are sharply different. Very interestingly, rRNAs of T. vaginalis are in size comparable to prokaryotic counterparts, with nearly all the eukaryote-specific rRNA expansion segments missing. These structures facilitate the dissection of evolution path for ribosomal proteins and $L̫VxnLE$L̫Vxnn of novel translation inhibitors.

    更新日期:2017-08-18
  • SMAD5 signaling: more than meets the nuclei
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    John Orlowski

    SMADs are essential transcriptional effectors of transforming growth factor-β (TGFβ)/TGFβ-related signaling that underlies embryonic development and adult homeostasis. A recent study by Fang et al. in Cell Research adds to this biological complexity by demonstrating an atypical cytoplasmic role for SMAD5 in modulating the bioenergetic homeostasis (i.e., glycolysis and mitochondrial respiration) of cells in response to fluctuations in intracellular pH that is independent of receptor signaling.

    更新日期:2017-08-18
  • Ythdc2 is an N 6-methyladenosine binding protein that regulates mammalian spermatogenesis
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Phillip J Hsu, Yunfei Zhu, Honghui Ma, Yueshuai Guo, Xiaodan Shi, Yuanyuan Liu, Meijie Qi, Zhike Lu, Hailing Shi, Jianying Wang, Yiwei Cheng, Guanzheng Luo, Qing Dai, Mingxi Liu, Xuejiang Guo, Jiahao Sha, Bin Shen, Chuan He

    N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m6A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m6A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m6A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m6A-binding protein that plays critical roles during spermatogenesis.

    更新日期:2017-08-18
  • Non-canonical regulation of SPL transcription factors by a human OTUB1-like deubiquitinase defines a new plant type rice associated with higher grain yield
    Cell Res. (IF 15.606) Pub Date : 2017-08-04
    Shuansuo Wang, Kun Wu, Qian Qian, Qian Liu, Qi Li, Yajun Pan, Yafeng Ye, Xueying Liu, Jing Wang, Jianqing Zhang, Shan Li, Yuejin Wu, Xiangdong Fu

    Achieving increased grain productivity has long been the overriding focus of cereal breeding programs. The ideotype approach has been used to improve rice yield potential at the International Rice Research Institute and in China. However, the genetic basis of yield-related traits in rice remains unclear. Here, we show that a major quantitative trait locus, qNPT1, acts through the determination of a 'new plant type' (NPT) architecture characterized by fewer tillers, sturdier culms and larger panicles, and it encodes a deubiquitinating enzyme with homology to human OTUB1. Downregulation of OsOTUB1 enhances meristematic activity, resulting in reduced tiller number, increased grain number, enhanced grain weight and a consequent increase in grain yield in rice. Unlike human OTUB1, OsOTUB1 can cleave both K48- and K63-linked polyubiquitin. OsOTUB1 interacts with the E2 ubiquitin-conjugating protein OsUBC13 and the squamosa promoter-binding protein-like transcription factor OsSPL14. OsOTUB1 and OsSPL14 share common target genes, and their physical interaction limits K63-linked ubiquitination (K63Ub) of OsSPL14, which in turn promotes K48Ub-dependent proteasomal degradation of OsSPL14. Conversely, loss-of-function of OsOTUB1 is correlated with the accumulation of high levels of OsSPL14, resulting in the NPT architecture. We also demonstrated that pyramiding of high-yielding npt1 and dep1-1 alleles provides a new strategy for increasing rice yield potential above what is currently achievable.

    更新日期:2017-08-07
  • Polar bodies are efficient donors for reconstruction of human embryos for potential mitochondrial replacement therapy
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Keliang Wu, Cuiqing Zhong, Tailai Chen, Xiaoyu Zhang, Wenrong Tao, Jingye Zhang, Hongchang Li, Han Zhao, Jinsong Li, Zi-Jiang Chen

    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.

    更新日期:2017-08-07
  • Clonal analysis reveals remarkable functional heterogeneity during hematopoietic stem cell emergence
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Hui Ye, Xiaobo Wang, Zongcheng Li, Fan Zhou, Xianlong Li, Yanli Ni, Weijing Zhang, Fuchou Tang, Bing Liu, Yu Lan

    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.

    更新日期:2017-08-07
  • Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Zhong Li, Matthew Brecher, Yong-Qiang Deng, Jing Zhang, Srilatha Sakamuru, Binbin Liu, Ruili Huang, Cheri A Koetzner, Christina A Allen, Susan A Jones, Haiying Chen, Na-Na Zhang, Min Tian2, Fengshan Gao, Qishan Lin, Nilesh Banavali, Jia Zhou, Nathan Boles, Menghang Xia, Laura D Kramer, Cheng-Feng Qin, Hongmin Li

    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.

    更新日期:2017-08-07
  • Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Young-hee Lee, Natalia Martin-Orozco, Peilin Zheng, Jing Li, Peng Zhang, Haidong Tan, Hyun Jung Park, Mira Jeong, Seon Hee Chang, Byung-Seok Kim, Wei Xiong, Wenjuan Zang, Li Guo, Yang Liu, Zhong-jun Dong, Willem W Overwijk, Patrick Hwu, Qing Yi, Larry Kwak, Zhiying Yang, Tak W Mak, Wei Li, Laszlo G Radvanyi, Ling Ni, Dongfang Liu, Chen Dong

    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.

    更新日期:2017-08-07
  • Dimeric structure of the uracil:proton symporter UraA provides mechanistic insights into the SLC4/23/26 transporters
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Xinzhe Yu, Guanghui Yang, Chuangye Yan, Javier L Baylon, Jing Jiang, He Fan, Guifeng Lu, Kazuya Hasegawa, Hideo Okumura, Tingliang Wang, Emad Tajkhorshid, Shuo Li, Nieng Yan

    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.

    更新日期:2017-08-07
  • Live cell screening platform identifies PPARδ as a regulator of cardiomyocyte proliferation and cardiac repair
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Ajit Magadum, Yishu Ding, Lan He, Teayoun Kim, Mohankrishna Dalvoy Vasudevarao, Qinqiang Long, Kevin Yang, Nadeera Wickramasinghe, Harsha V Renikunta, Nicole Dubois, Gilbert Weidinger, Qinglin Yang, Felix B Engel

    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.

    更新日期:2017-08-07
  • Cryo-EM structure and biochemical analysis reveal the basis of the functional difference between human PI3KC3-C1 and -C2
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Meisheng Ma, Jun-Jie Liu, Yan Li, Yuwei Huang, Na Ta, Yang Chen, Hua Fu, Ming-Da Ye, Yuehe Ding, Weijiao Huang, Jia Wang, Meng-Qiu Dong, Li Yu, Hong-Wei Wang

    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.

    更新日期:2017-08-07
  • Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Fan Guo, Lin Li, Jingyun Li, Xinglong Wu, Boqiang Hu, Ping Zhu, Lu Wen, Fuchou Tang

    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.

    更新日期:2017-08-07
  • It takes two to transport via an elevator
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Bernadette Byrne

    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.

    更新日期:2017-08-07
  • Repolarizing macrophages improves breast cancer therapy
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Luca Cassetta1 and Jeffrey W Pollard

    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.

    更新日期:2017-08-07
  • Reassembling embryos in vitro from component stem cells
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Caroline Kubaczka, George Q Daley

    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.

    更新日期:2017-08-07
  • Cardiomyocyte proliferation: remove brakes and push accelerators
    Cell Res. (IF 15.606) Pub Date : 2017-08-06
    Lingjuan He, Bin Zhou

    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.

    更新日期:2017-08-07
  • Cryo-EM structure and biochemical analysis reveal the basis of the functional difference between human PI3KC3-C1 and -C2
    Cell Res. (IF 15.606) Pub Date : 2017-07-21
    Meisheng Ma, Jun-Jie Liu, Yan Li, Yuwei Huang, Na Ta, Yang Chen, Hua Fu, Ming-Da Ye, Yuehe Ding, Weijiao Huang, Jia Wang, Meng-Qiu Dong, Li Yu, Hong-Wei Wang

    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.

    更新日期:2017-07-25
  • NLRP9b: a novel RNA-sensing inflammasome complex
    Cell Res. (IF 15.606) Pub Date : 2017-07-21
    Chinh Ngo, Si Ming Man

    Inflammasome sensors recognize pathogens and danger signals and assemble an immune signaling complex, which induces the secretion of pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. A new study published in Nature now describes a new inflammasome sensor NLRP9b in intestinal epithelial cells, which in concert with the RNA sensor DHX9, recognize short dsRNA from Rotavirus.

    更新日期:2017-07-25
  • The genetics of tiger pelage color variations
    Cell Res. (IF 15.606) Pub Date : 2017-07-22
    Xiao Xu, Gui-Xin Dong, Anne Schmidt-Küntzel, Xue-Li Zhang, Yan Zhuang, Run Fang, Xin Sun, Xue-Song Hu, Tian-You Zhang, Han-Dong Yang, De-Lu Zhang, Laurie Marker, Zheng-Fan Jiang, Ruiqiang Li, Shu-Jin Luo

    The tiger (Panthera tigris) is most recognized for its dark stripes against an orange background. Less well known are three other pelage color variants: white, golden and stripeless snow white (Figure 1A). The white tiger is a polymorphism that was first seen among wild Bengal tigers (P. t. tigris) in India, with white fur and sepia brown stripes1. The golden tiger, also first sighted in the jungle in India, has a blonde color tone with pale golden fur and red-brown rather than black stripes2. The snow white tiger is almost completely white, with faint to nearly nonexistent narrow stripes on the trunk and diluted sepia brown rings on the tail2. During the past century, the number of wild tigers in the world has severely declined primarily due to anthropogenic reasons, and except for the wild-type orange tigers, all other variants now exist only in captivity.

    更新日期:2017-07-22
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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