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  • 1
    Publication Date: 2018-09-18
    Description: The epithelial–mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM–ESRP1 coregulated exons identifies guanine–uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis -elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.
    Print ISSN: 1355-8382
    Electronic ISSN: 1469-9001
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2018-01-09
    Description: Three-component fermions with surface Fermi arcs in tungsten carbide Three-component fermions with surface Fermi arcs in tungsten carbide, Published online: 08 January 2018; doi:10.1038/s41567-017-0021-8 Triply degenerate electronic structure—three-component fermions—protected by crystal symmetries is observed in tungsten carbide. The observed Fermi arcs associated with the surface states provide evidence of the non-trivial topology of the states.
    Print ISSN: 1745-2473
    Electronic ISSN: 1745-2481
    Topics: Physics
    Published by Springer Nature
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  • 3
    Publication Date: 2011-04-19
    Description: The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligand-receptor interactions with killer-cell immunoglobulin-like receptors. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV, and with levels of HLA-C messenger RNA transcripts and cell-surface expression, but the mechanism underlying its varied expression is unknown. We proposed that the -35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C. Here we show that variation within the 3' untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3' UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kulkarni, Smita -- Savan, Ram -- Qi, Ying -- Gao, Xiaojiang -- Yuki, Yuko -- Bass, Sara E -- Martin, Maureen P -- Hunt, Peter -- Deeks, Steven G -- Telenti, Amalio -- Pereyra, Florencia -- Goldstein, David -- Wolinsky, Steven -- Walker, Bruce -- Young, Howard A -- Carrington, Mary -- 5-M01-RR-00722/RR/NCRR NIH HHS/ -- HHSN261200800001E/CO/NCI NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- N02-CP-55504/CP/NCI NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- R01-DA04334/DA/NIDA NIH HHS/ -- R01-DA12568/DA/NIDA NIH HHS/ -- U01-AI-35039/AI/NIAID NIH HHS/ -- U01-AI-35040/AI/NIAID NIH HHS/ -- U01-AI-35041/AI/NIAID NIH HHS/ -- U01-AI-35042/AI/NIAID NIH HHS/ -- U01-AI-35043/AI/NIAID NIH HHS/ -- U01-AI-37613/AI/NIAID NIH HHS/ -- U01-AI-37984/AI/NIAID NIH HHS/ -- UL1 RR024131/RR/NCRR NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Apr 28;472(7344):495-8. doi: 10.1038/nature09914. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499264" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Alleles ; Base Sequence ; Cell Line ; *Gene Expression Regulation/genetics/immunology ; Genes, Reporter/genetics ; HIV/*immunology ; HIV Infections/*genetics/*immunology/therapy ; HLA-C Antigens/*genetics ; Humans ; MicroRNAs/*genetics ; Polymorphism, Single Nucleotide/genetics ; Viral Load
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-08-08
    Description: Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nillegoda, Nadinath B -- Kirstein, Janine -- Szlachcic, Anna -- Berynskyy, Mykhaylo -- Stank, Antonia -- Stengel, Florian -- Arnsburg, Kristin -- Gao, Xuechao -- Scior, Annika -- Aebersold, Ruedi -- Guilbride, D Lys -- Wade, Rebecca C -- Morimoto, Richard I -- Mayer, Matthias P -- Bukau, Bernd -- England -- Nature. 2015 Aug 13;524(7564):247-51. doi: 10.1038/nature14884. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany. ; Leibniz-Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany. ; Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany. ; 1] Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany [2] Heidelberg Graduate School of Mathematical and Computational Methods for the Sciences, Heidelberg University, 69120 Heidelberg, Germany. ; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland. ; 1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, 8057 Zurich, Switzerland. ; 1] Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany [2] Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany [3] Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany. ; Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245380" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/*metabolism ; HSP110 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/chemistry/*metabolism ; Humans ; Models, Molecular ; *Protein Aggregates ; Protein Aggregation, Pathological/metabolism/prevention & control ; Protein Binding ; Protein Structure, Tertiary ; Static Electricity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2015-07-23
    Description: G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a approximately 20 degrees rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Yanyong -- Zhou, X Edward -- Gao, Xiang -- He, Yuanzheng -- Liu, Wei -- Ishchenko, Andrii -- Barty, Anton -- White, Thomas A -- Yefanov, Oleksandr -- Han, Gye Won -- Xu, Qingping -- de Waal, Parker W -- Ke, Jiyuan -- Tan, M H Eileen -- Zhang, Chenghai -- Moeller, Arne -- West, Graham M -- Pascal, Bruce D -- Van Eps, Ned -- Caro, Lydia N -- Vishnivetskiy, Sergey A -- Lee, Regina J -- Suino-Powell, Kelly M -- Gu, Xin -- Pal, Kuntal -- Ma, Jinming -- Zhi, Xiaoyong -- Boutet, Sebastien -- Williams, Garth J -- Messerschmidt, Marc -- Gati, Cornelius -- Zatsepin, Nadia A -- Wang, Dingjie -- James, Daniel -- Basu, Shibom -- Roy-Chowdhury, Shatabdi -- Conrad, Chelsie E -- Coe, Jesse -- Liu, Haiguang -- Lisova, Stella -- Kupitz, Christopher -- Grotjohann, Ingo -- Fromme, Raimund -- Jiang, Yi -- Tan, Minjia -- Yang, Huaiyu -- Li, Jun -- Wang, Meitian -- Zheng, Zhong -- Li, Dianfan -- Howe, Nicole -- Zhao, Yingming -- Standfuss, Jorg -- Diederichs, Kay -- Dong, Yuhui -- Potter, Clinton S -- Carragher, Bridget -- Caffrey, Martin -- Jiang, Hualiang -- Chapman, Henry N -- Spence, John C H -- Fromme, Petra -- Weierstall, Uwe -- Ernst, Oliver P -- Katritch, Vsevolod -- Gurevich, Vsevolod V -- Griffin, Patrick R -- Hubbell, Wayne L -- Stevens, Raymond C -- Cherezov, Vadim -- Melcher, Karsten -- Xu, H Eric -- DK071662/DK/NIDDK NIH HHS/ -- EY005216/EY/NEI NIH HHS/ -- EY011500/EY/NEI NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM077561/GM/NIGMS NIH HHS/ -- GM095583/GM/NIGMS NIH HHS/ -- GM097463/GM/NIGMS NIH HHS/ -- GM102545/GM/NIGMS NIH HHS/ -- GM103310/GM/NIGMS NIH HHS/ -- GM104212/GM/NIGMS NIH HHS/ -- GM108635/GM/NIGMS NIH HHS/ -- P30EY000331/EY/NEI NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P41RR001209/RR/NCRR NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 DK066202/DK/NIDDK NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 EY011500/EY/NEI NIH HHS/ -- R01 GM087413/GM/NIGMS NIH HHS/ -- R01 GM109955/GM/NIGMS NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):561-7. doi: 10.1038/nature14656. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA. ; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany. ; Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; The National Resource for Automated Molecular Microscopy, New York Structural Biology Center, New York, New York 10027, USA. ; Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA. ; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA [2] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, Arizona State University, Tempe, Arizona 85287, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Beijing Computational Science Research Center, Haidian District, Beijing 10084, China. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA. ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; School of Medicine and School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. ; 1] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA [2] Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA. ; Laboratory of Biomolecular Research at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biology, Universitat Konstanz, 78457 Konstanz, Germany. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; 1] Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany [2] Centre for Ultrafast Imaging, 22761 Hamburg, Germany. ; 1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [2] Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200343" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrestin/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry/metabolism ; Humans ; Lasers ; Mice ; Models, Molecular ; Multiprotein Complexes/biosynthesis/chemistry/metabolism ; Protein Binding ; Reproducibility of Results ; Rhodopsin/*chemistry/*metabolism ; Signal Transduction ; X-Rays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2016-02-18
    Description: Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mei, Yuan -- Monteiro, Patricia -- Zhou, Yang -- Kim, Jin-Ah -- Gao, Xian -- Fu, Zhanyan -- Feng, Guoping -- R01MH097104/MH/NIMH NIH HHS/ -- England -- Nature. 2016 Feb 25;530(7591):481-4. doi: 10.1038/nature16971. Epub 2016 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; PhD Programme in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Masaschusetts 02142, USA. ; Key Laboratory of Brain Functional Genomics (Ministry of Education &Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitve Science, East China Normal University, Shanghai 200062, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26886798" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2015-10-13
    Description: The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine (m(6)A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m(6)A along mRNAs results in relatively less methylation in the 5' untranslated region (5'UTR) compared to other regions. However, whether and how 5'UTR methylation is regulated is poorly understood. Despite the crucial role of the 5'UTR in translation initiation, very little is known about whether m(6)A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5'UTR of newly transcribed mRNAs are preferentially methylated. We find that the dynamic 5'UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m(6)A 'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5'UTR methylation of stress-induced transcripts by limiting the m(6)A 'eraser' FTO from demethylation. Remarkably, the increased 5'UTR methylation in the form of m(6)A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m(6)A modification site in the 5'UTR enables translation initiation independent of the 5' end N(7)-methylguanosine cap. The elucidation of the dynamic features of 5'UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m(6)A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Jun -- Wan, Ji -- Gao, Xiangwei -- Zhang, Xingqian -- Jaffrey, Samie R -- Qian, Shu-Bing -- DA037150/DA/NIDA NIH HHS/ -- DP2OD006449/OD/NIH HHS/ -- R01AG042400/AG/NIA NIH HHS/ -- England -- Nature. 2015 Oct 22;526(7574):591-4. doi: 10.1038/nature15377. Epub 2015 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA. ; Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York City, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26458103" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Adenosine/*analogs & derivatives/metabolism ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Fibroblasts/cytology/metabolism ; *Gene Expression Regulation ; HSP70 Heat-Shock Proteins/genetics ; *Heat-Shock Response/genetics ; *Methylation ; Mice ; Mixed Function Oxygenases/antagonists & inhibitors/metabolism ; Oxo-Acid-Lyases/antagonists & inhibitors/metabolism ; *Peptide Chain Initiation, Translational ; RNA Caps/metabolism ; RNA, Messenger/genetics/*metabolism ; RNA-Binding Proteins/metabolism ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2018-04-05
    Description: Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear. Herein, we determined CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients and found that CYP2E1-mediated DEN metabolic activity was significantly elevated with a 43.3% positive rate, and clinicopathologic parameters did not affect the activity. Then, using a Sprague-Dawley rat liver tumor model induced by DEN, the relationship between CYP2E1 constitutive/inhibited activity and hepatocarcinogenesis was explored. The results showed that the CYP2E1 constitutive activity was strongly correlated with tumor incidence and severity of liver tumorigenesis (nodule numbers and size), whereas inhibition of CYP2E1 activity decreased hepatocyte proliferation, liver injury, and liver carcinogenesis in the presence of DEN. In conclusion, the higher CYP2E1 activity would lead to an increased incidence of HCC as a result of CYP2E1-mediated DEN activation. Therefore, higher CYP2E1 activity might be a risk factor for HCC induced by DEN.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
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  • 9
    Publication Date: 2018-10-23
    Description: Genome-wide association studies have recently illuminated that WDFY4 is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of WDFY4 in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated Wdfy4 B lymphocyte conditional knockout ( Wdfy4 -CKO) mice and found that loss of Wdfy4 led to a decrease in number of total B cells and several subpopulations of B cells in the periphery and a defect in the transition from the pro– to pre–B cell stage in bone marrow. Also, Wdfy4 -CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in Wdfy4 -CKO mice, with significantly diminished pristane-elicited production of autoantibodies and glomerulonephritis. Genetic silencing of WDFY4 in B cells increased lipidation of LC3 independent of p62 and Beclin1, which are essential proteins of canonical autophagy. Our in vivo and in vitro data suggest that WDFY4 facilitates noncanonical autophagic activity. Our findings provide a novel functional link underlying the mechanism of SLE in which WDFY4 influences B cell fate via noncanonical autophagy.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 10
    Publication Date: 2018-10-26
    Description: Clinical observations indicate that the paramedian region of the thalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we found that glutamatergic neurons of the paraventricular thalamus (PVT) exhibited high activities during wakefulness. Suppression of PVT neuronal activity caused a reduction in wakefulness, whereas activation of PVT neurons induced a transition from sleep to wakefulness and an acceleration of emergence from general anesthesia. Moreover, our findings indicate that the PVT–nucleus accumbens projections and hypocretin neurons in the lateral hypothalamus to PVT glutamatergic neurons’ projections are the effector pathways for wakefulness control. These results demonstrate that the PVT is a key wakefulness-controlling nucleus in the thalamus.
    Keywords: Neuroscience
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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