ALBERT

Description: The association of genetic variation with disease and drug response, and improvements in nucleic acid technologies, have given great optimism for the impact of 'genomic medicine'. However, the formidable size of the diploid human genome, approximately 6 gigabases, has prevented the routine application of sequencing methods to deciphering complete individual human genomes. To realize the full potential of genomics for human health, this limitation must be overcome. Here we report the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing in picolitre-size reaction vessels. This sequence was completed in two months at approximately one-hundredth of the cost of traditional capillary electrophoresis methods. Comparison of the sequence to the reference genome led to the identification of 3.3 million single nucleotide polymorphisms, of which 10,654 cause amino-acid substitution within the coding sequence. In addition, we accurately identified small-scale (2-40,000 base pair (bp)) insertion and deletion polymorphism as well as copy number variation resulting in the large-scale gain and loss of chromosomal segments ranging from 26,000 to 1.5 million base pairs. Overall, these results agree well with recent results of sequencing of a single individual by traditional methods. However, in addition to being faster and significantly less expensive, this sequencing technology avoids the arbitrary loss of genomic sequences inherent in random shotgun sequencing by bacterial cloning because it amplifies DNA in a cell-free system. As a result, we further demonstrate the acquisition of novel human sequence, including novel genes not previously identified by traditional genomic sequencing. This is the first genome sequenced by next-generation technologies. Therefore it is a pilot for the future challenges of 'personalized genome sequencing'.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, David A -- Srinivasan, Maithreyan -- Egholm, Michael -- Shen, Yufeng -- Chen, Lei -- McGuire, Amy -- He, Wen -- Chen, Yi-Ju -- Makhijani, Vinod -- Roth, G Thomas -- Gomes, Xavier -- Tartaro, Karrie -- Niazi, Faheem -- Turcotte, Cynthia L -- Irzyk, Gerard P -- Lupski, James R -- Chinault, Craig -- Song, Xing-zhi -- Liu, Yue -- Yuan, Ye -- Nazareth, Lynne -- Qin, Xiang -- Muzny, Donna M -- Margulies, Marcel -- Weinstock, George M -- Gibbs, Richard A -- Rothberg, Jonathan M -- U54 HG003273/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Apr 17;452(7189):872-6. doi: 10.1038/nature06884.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18421352" target="_blank"〉PubMed〈/a〉

Description: Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695978/" 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/PMC2695978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cadwell, Ken -- Liu, John Y -- Brown, Sarah L -- Miyoshi, Hiroyuki -- Loh, Joy -- Lennerz, Jochen K -- Kishi, Chieko -- Kc, Wumesh -- Carrero, Javier A -- Hunt, Steven -- Stone, Christian D -- Brunt, Elizabeth M -- Xavier, Ramnik J -- Sleckman, Barry P -- Li, Ellen -- Mizushima, Noboru -- Stappenbeck, Thaddeus S -- Virgin, Herbert W 4th -- AI062773/AI/NIAID NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 DK043351-18/DK/NIDDK NIH HHS/ -- P30 DK052574-09/DK/NIDDK NIH HHS/ -- P30 DK52574/DK/NIDDK NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- R01 AI062832/AI/NIAID NIH HHS/ -- R01 AI062832-04/AI/NIAID NIH HHS/ -- T32 AR007279/AR/NIAMS NIH HHS/ -- T32 AR007279-30/AR/NIAMS NIH HHS/ -- T32 AR07279/AR/NIAMS NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- U54 AI057160-010005/AI/NIAID NIH HHS/ -- U54 AI057160-05S10018/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 13;456(7219):259-63. doi: 10.1038/nature07416. Epub 2008 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849966" target="_blank"〉PubMed〈/a〉

Description: The recent emergence of highly pathogenic avian influenza A virus strains with subtype H5N1 pose a global threat to human health. Elucidation of the underlying mechanisms of viral replication is critical for development of anti-influenza virus drugs. The influenza RNA-dependent RNA polymerase (RdRp) heterotrimer has crucial roles in viral RNA replication and transcription. It contains three proteins: PA, PB1 and PB2. PB1 harbours polymerase and endonuclease activities and PB2 is responsible for cap binding; PA is implicated in RNA replication and proteolytic activity, although its function is less clearly defined. Here we report the 2.9 angstrom structure of avian H5N1 influenza A virus PA (PA(C), residues 257-716) in complex with the PA-binding region of PB1 (PB1(N), residues 1-25). PA(C) has a fold resembling a dragon's head with PB1(N) clamped into its open 'jaws'. PB1(N) is a known inhibitor that blocks assembly of the polymerase heterotrimer and abolishes viral replication. Our structure provides details for the binding of PB1(N) to PA(C) at the atomic level, demonstrating a potential target for novel anti-influenza therapeutics. We also discuss a potential nucleotide binding site and the roles of some known residues involved in polymerase activity. Furthermore, to explore the role of PA in viral replication and transcription, we propose a model for the influenza RdRp heterotrimer by comparing PA(C) with the lambda3 reovirus polymerase structure, and docking the PA(C) structure into an available low resolution electron microscopy map.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Xiaojing -- Zhou, Jie -- Bartlam, Mark -- Zhang, Rongguang -- Ma, Jianyuan -- Lou, Zhiyong -- Li, Xuemei -- Li, Jingjing -- Joachimiak, Andrzej -- Zeng, Zonghao -- Ge, Ruowen -- Rao, Zihe -- Liu, Yingfang -- England -- Nature. 2008 Aug 28;454(7208):1123-6. doi: 10.1038/nature07120. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615018" target="_blank"〉PubMed〈/a〉

Description: The heterotrimeric influenza virus polymerase, containing the PA, PB1 and PB2 proteins, catalyses viral RNA replication and transcription in the nucleus of infected cells. PB1 holds the polymerase active site and reportedly harbours endonuclease activity, whereas PB2 is responsible for cap binding. The PA amino terminus is understood to be the major functional part of the PA protein and has been implicated in several roles, including endonuclease and protease activities as well as viral RNA/complementary RNA promoter binding. Here we report the 2.2 angstrom (A) crystal structure of the N-terminal 197 residues of PA, termed PA(N), from an avian influenza H5N1 virus. The PA(N) structure has an alpha/beta architecture and reveals a bound magnesium ion coordinated by a motif similar to the (P)DX(N)(D/E)XK motif characteristic of many endonucleases. Structural comparisons and mutagenesis analysis of the motif identified in PA(N) provide further evidence that PA(N) holds an endonuclease active site. Furthermore, functional analysis with in vivo ribonucleoprotein reconstitution and direct in vitro endonuclease assays strongly suggest that PA(N) holds the endonuclease active site and has critical roles in endonuclease activity of the influenza virus polymerase, rather than PB1. The high conservation of this endonuclease active site among influenza strains indicates that PA(N) is an important target for the design of new anti-influenza therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yuan, Puwei -- Bartlam, Mark -- Lou, Zhiyong -- Chen, Shoudeng -- Zhou, Jie -- He, Xiaojing -- Lv, Zongyang -- Ge, Ruowen -- Li, Xuemei -- Deng, Tao -- Fodor, Ervin -- Rao, Zihe -- Liu, Yingfang -- G0700848/Medical Research Council/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):909-13. doi: 10.1038/nature07720. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194458" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yi -- England -- Nature. 2009 Sep 24;461(7263):484-5. doi: 10.1038/461484a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779441" target="_blank"〉PubMed〈/a〉

Description: The major facilitator superfamily (MFS) transporters are an ancient and widespread family of secondary active transporters. In Escherichia coli, the uptake of l-fucose, a source of carbon for microorganisms, is mediated by an MFS proton symporter, FucP. Despite intensive study of the MFS transporters, atomic structure information is only available on three proteins and the outward-open conformation has yet to be captured. Here we report the crystal structure of FucP at 3.1 A resolution, which shows that it contains an outward-open, amphipathic cavity. The similarly folded amino and carboxyl domains of FucP have contrasting surface features along the transport path, with negative electrostatic potential on the N domain and hydrophobic surface on the C domain. FucP only contains two acidic residues along the transport path, Asp 46 and Glu 135, which can undergo cycles of protonation and deprotonation. Their essential role in active transport is supported by both in vivo and in vitro experiments. Structure-based biochemical analyses provide insights into energy coupling, substrate recognition and the transport mechanism of FucP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dang, Shangyu -- Sun, Linfeng -- Huang, Yongjian -- Lu, Feiran -- Liu, Yufeng -- Gong, Haipeng -- Wang, Jiawei -- Yan, Nieng -- England -- Nature. 2010 Oct 7;467(7316):734-8. doi: 10.1038/nature09406. Epub 2010 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20877283" target="_blank"〉PubMed〈/a〉

Description: Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303590/" 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/PMC4303590/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xianqin -- Bogunovic, Dusan -- Payelle-Brogard, Beatrice -- Francois-Newton, Veronique -- Speer, Scott D -- Yuan, Chao -- Volpi, Stefano -- Li, Zhi -- Sanal, Ozden -- Mansouri, Davood -- Tezcan, Ilhan -- Rice, Gillian I -- Chen, Chunyuan -- Mansouri, Nahal -- Mahdaviani, Seyed Alireza -- Itan, Yuval -- Boisson, Bertrand -- Okada, Satoshi -- Zeng, Lu -- Wang, Xing -- Jiang, Hui -- Liu, Wenqiang -- Han, Tiantian -- Liu, Delin -- Ma, Tao -- Wang, Bo -- Liu, Mugen -- Liu, Jing-Yu -- Wang, Qing K -- Yalnizoglu, Dilek -- Radoshevich, Lilliana -- Uze, Gilles -- Gros, Philippe -- Rozenberg, Flore -- Zhang, Shen-Ying -- Jouanguy, Emmanuelle -- Bustamante, Jacinta -- Garcia-Sastre, Adolfo -- Abel, Laurent -- Lebon, Pierre -- Notarangelo, Luigi D -- Crow, Yanick J -- Boisson-Dupuis, Stephanie -- Casanova, Jean-Laurent -- Pellegrini, Sandra -- 1P01AI076210-01A1/AI/NIAID NIH HHS/ -- 309449/European Research Council/International -- 8UL1TR000043/TR/NCATS NIH HHS/ -- P01 AI076210/AI/NIAID NIH HHS/ -- P01 AI090935/AI/NIAID NIH HHS/ -- P01AI090935/AI/NIAID NIH HHS/ -- R00 AI106942/AI/NIAID NIH HHS/ -- R00AI106942-02/AI/NIAID NIH HHS/ -- R01 AI035237/AI/NIAID NIH HHS/ -- R37 AI095983/AI/NIAID NIH HHS/ -- R37AI095983/AI/NIAID NIH HHS/ -- U19 AI083025/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- UL1 TR000043/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 1;517(7532):89-93. doi: 10.1038/nature13801. Epub 2014 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. ; 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA [2] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France. ; 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Microbiology Training Area, Graduate School of Biomedical Sciences of Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA [2] Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy. ; Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, Turkey. ; Division of Infectious Diseases and Clinical Immunology, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 4739 Teheran, Iran. ; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK. ; Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha 410013, China. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA. ; BGI-Shenzhen, Shenzhen 518083, China. ; Sangzhi County People's Hospital, Sangzhi 427100, China. ; Genetics Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, Hubei 430070, China. ; 1] Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China [2] Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. ; Institut Pasteur, Bacteria-Cell Interactions Unit, 75724 Paris, France. ; CNRS UMR5235, Montpellier II University, Place Eugene Bataillon, 34095 Montpellier, France. ; Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada. ; Paris Descartes University, 75006 Paris, France. ; 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France. ; 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France. ; 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA [2] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [3] Paris Descartes University, Imagine Institute, 75015 Paris, France. ; Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; 1] Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, 75006 Paris, France. ; 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] Howard Hughes Medical Institute, New York, New York 10065, USA [4] Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France [5]. ; 1] Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25307056" target="_blank"〉PubMed〈/a〉

Description: The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Yue -- Li, Wenfei -- Li, Jian -- Wang, Jiawei -- Ge, Jingpeng -- Xu, Duo -- Liu, Yanjing -- Wu, Kaiqi -- Zeng, Qingyin -- Wu, Jia-Wei -- Tian, Changlin -- Zhou, Bing -- Yang, Maojun -- England -- Nature. 2012 Nov 15;491(7424):478-82. doi: 10.1038/nature11541. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086143" target="_blank"〉PubMed〈/a〉

Description: Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Zhigang -- Huang, Kevin -- Cai, Chaochao -- Cai, Lingbo -- Jiang, Chun-yan -- Feng, Yun -- Liu, Zhenshan -- Zeng, Qiao -- Cheng, Liming -- Sun, Yi E -- Liu, Jia-yin -- Horvath, Steve -- Fan, Guoping -- P01 HD006576/HD/NICHD NIH HHS/ -- P30 HD004612/HD/NICHD NIH HHS/ -- P50 DA005010/DA/NIDA NIH HHS/ -- England -- Nature. 2013 Aug 29;500(7464):593-7. doi: 10.1038/nature12364. Epub 2013 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China. xuezhigang75@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23892778" target="_blank"〉PubMed〈/a〉

Description: Genomic imprinting is an allele-specific gene expression system that is important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation. Although it is well known that the de novo DNA methyltransferases Dnmt3a and Dnmt3b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains unclear. Tet1 is one of the ten-eleven translocation family proteins, which have the capacity to oxidize 5-methylcytosine (5mC), specifically expressed in reprogramming PGCs. Here we report that Tet1 has a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1 knockout males and wild-Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal loss of Tet1 function. Genome-wide DNA methylation analysis of embryonic day 13.5 PGCs and sperm of Tet1 knockout mice revealed hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Analysis of the DNA methylation dynamics in reprogramming PGCs indicates that Tet1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage. Furthermore, we provide evidence supporting the role of Tet1 in the erasure of paternal imprints in the female germ line. Thus, our study establishes a critical function of Tet1 in the erasure of genomic imprinting.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957231/" 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/PMC3957231/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamaguchi, Shinpei -- Shen, Li -- Liu, Yuting -- Sendler, Damian -- Zhang, Yi -- U01 DK089565/DK/NIDDK NIH HHS/ -- U01DK089565/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):460-4. doi: 10.1038/nature12805. Epub 2013 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA [3] Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; 1] Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA [3] Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts 02115, USA [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [5] Harvard Stem Cell Institute, WAB-149G, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24291790" target="_blank"〉PubMed〈/a〉