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  • 1
    Publication Date: 2014-03-29
    Description: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748/" 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/PMC4529748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉FANTOM Consortium and the RIKEN PMI and CLST (DGT) -- Forrest, Alistair R R -- Kawaji, Hideya -- Rehli, Michael -- Baillie, J Kenneth -- de Hoon, Michiel J L -- Haberle, Vanja -- Lassmann, Timo -- Kulakovskiy, Ivan V -- Lizio, Marina -- Itoh, Masayoshi -- Andersson, Robin -- Mungall, Christopher J -- Meehan, Terrence F -- Schmeier, Sebastian -- Bertin, Nicolas -- Jorgensen, Mette -- Dimont, Emmanuel -- Arner, Erik -- Schmidl, Christian -- Schaefer, Ulf -- Medvedeva, Yulia A -- Plessy, Charles -- Vitezic, Morana -- Severin, Jessica -- Semple, Colin A -- Ishizu, Yuri -- Young, Robert S -- Francescatto, Margherita -- Alam, Intikhab -- Albanese, Davide -- Altschuler, Gabriel M -- Arakawa, Takahiro -- Archer, John A C -- Arner, Peter -- Babina, Magda -- Rennie, Sarah -- Balwierz, Piotr J -- Beckhouse, Anthony G -- Pradhan-Bhatt, Swati -- Blake, Judith A -- Blumenthal, Antje -- Bodega, Beatrice -- Bonetti, Alessandro -- Briggs, James -- Brombacher, Frank -- Burroughs, A Maxwell -- Califano, Andrea -- Cannistraci, Carlo V -- Carbajo, Daniel -- Chen, Yun -- Chierici, Marco -- Ciani, Yari -- Clevers, Hans C -- Dalla, Emiliano -- Davis, Carrie A -- Detmar, Michael -- Diehl, Alexander D -- Dohi, Taeko -- Drablos, Finn -- Edge, Albert S B -- Edinger, Matthias -- Ekwall, Karl -- Endoh, Mitsuhiro -- Enomoto, Hideki -- Fagiolini, Michela -- Fairbairn, Lynsey -- Fang, Hai -- Farach-Carson, Mary C -- Faulkner, Geoffrey J -- Favorov, Alexander V -- Fisher, Malcolm E -- Frith, Martin C -- Fujita, Rie -- Fukuda, Shiro -- Furlanello, Cesare -- Furino, Masaaki -- Furusawa, Jun-ichi -- Geijtenbeek, Teunis B -- Gibson, Andrew P -- Gingeras, Thomas -- Goldowitz, Daniel -- Gough, Julian -- Guhl, Sven -- Guler, Reto -- Gustincich, Stefano -- Ha, Thomas J -- Hamaguchi, Masahide -- Hara, Mitsuko -- Harbers, Matthias -- Harshbarger, Jayson -- Hasegawa, Akira -- Hasegawa, Yuki -- Hashimoto, Takehiro -- Herlyn, Meenhard -- Hitchens, Kelly J -- Ho Sui, Shannan J -- Hofmann, Oliver M -- Hoof, Ilka -- Hori, Furni -- Huminiecki, Lukasz -- Iida, Kei -- Ikawa, Tomokatsu -- Jankovic, Boris R -- Jia, Hui -- Joshi, Anagha -- Jurman, Giuseppe -- Kaczkowski, Bogumil -- Kai, Chieko -- Kaida, Kaoru -- Kaiho, Ai -- Kajiyama, Kazuhiro -- Kanamori-Katayama, Mutsumi -- Kasianov, Artem S -- Kasukawa, Takeya -- Katayama, Shintaro -- Kato, Sachi -- Kawaguchi, Shuji -- Kawamoto, Hiroshi -- Kawamura, Yuki I -- Kawashima, Tsugumi -- Kempfle, Judith S -- Kenna, Tony J -- Kere, Juha -- Khachigian, Levon M -- Kitamura, Toshio -- Klinken, S Peter -- Knox, Alan J -- Kojima, Miki -- Kojima, Soichi -- Kondo, Naoto -- Koseki, Haruhiko -- Koyasu, Shigeo -- Krampitz, Sarah -- Kubosaki, Atsutaka -- Kwon, Andrew T -- Laros, Jeroen F J -- Lee, Weonju -- Lennartsson, Andreas -- Li, Kang -- Lilje, Berit -- Lipovich, Leonard -- Mackay-Sim, Alan -- Manabe, Ri-ichiroh -- Mar, Jessica C -- Marchand, Benoit -- Mathelier, Anthony -- Mejhert, Niklas -- Meynert, Alison -- Mizuno, Yosuke -- de Lima Morais, David A -- Morikawa, Hiromasa -- Morimoto, Mitsuru -- Moro, Kazuyo -- Motakis, Efthymios -- Motohashi, Hozumi -- Mummery, Christine L -- Murata, Mitsuyoshi -- Nagao-Sato, Sayaka -- Nakachi, Yutaka -- Nakahara, Fumio -- Nakamura, Toshiyuki -- Nakamura, Yukio -- Nakazato, Kenichi -- van Nimwegen, Erik -- Ninomiya, Noriko -- Nishiyori, Hiromi -- Noma, Shohei -- Noazaki, Tadasuke -- Ogishima, Soichi -- Ohkura, Naganari -- Ohimiya, Hiroko -- Ohno, Hiroshi -- Ohshima, Mitsuhiro -- Okada-Hatakeyama, Mariko -- Okazaki, Yasushi -- Orlando, Valerio -- Ovchinnikov, Dmitry A -- Pain, Arnab -- Passier, Robert -- Patrikakis, Margaret -- Persson, Helena -- Piazza, Silvano -- Prendergast, James G D -- Rackham, Owen J L -- Ramilowski, Jordan A -- Rashid, Mamoon -- Ravasi, Timothy -- Rizzu, Patrizia -- Roncador, Marco -- Roy, Sugata -- Rye, Morten B -- Saijyo, Eri -- Sajantila, Antti -- Saka, Akiko -- Sakaguchi, Shimon -- Sakai, Mizuho -- Sato, Hiroki -- Savvi, Suzana -- Saxena, Alka -- Schneider, Claudio -- Schultes, Erik A -- Schulze-Tanzil, Gundula G -- Schwegmann, Anita -- Sengstag, Thierry -- Sheng, Guojun -- Shimoji, Hisashi -- Shimoni, Yishai -- Shin, Jay W -- Simon, Christophe -- Sugiyama, Daisuke -- Sugiyama, Takaai -- Suzuki, Masanori -- Suzuki, Naoko -- Swoboda, Rolf K -- 't Hoen, Peter A C -- Tagami, Michihira -- Takahashi, Naoko -- Takai, Jun -- Tanaka, Hiroshi -- Tatsukawa, Hideki -- Tatum, Zuotian -- Thompson, Mark -- Toyodo, Hiroo -- Toyoda, Tetsuro -- Valen, Elvind -- van de Wetering, Marc -- van den Berg, Linda M -- Verado, Roberto -- Vijayan, Dipti -- Vorontsov, Ilya E -- Wasserman, Wyeth W -- Watanabe, Shoko -- Wells, Christine A -- Winteringham, Louise N -- Wolvetang, Ernst -- Wood, Emily J -- Yamaguchi, Yoko -- Yamamoto, Masayuki -- Yoneda, Misako -- Yonekura, Yohei -- Yoshida, Shigehiro -- Zabierowski, Susan E -- Zhang, Peter G -- Zhao, Xiaobei -- Zucchelli, Silvia -- Summers, Kim M -- Suzuki, Harukazu -- Daub, Carsten O -- Kawai, Jun -- Heutink, Peter -- Hide, Winston -- Freeman, Tom C -- Lenhard, Boris -- Bajic, Vladimir B -- Taylor, Martin S -- Makeev, Vsevolod J -- Sandelin, Albin -- Hume, David A -- Carninci, Piero -- Hayashizaki, Yoshihide -- BB/F003722/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G022771/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I001107/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_PC_U127597124/Medical Research Council/United Kingdom -- MC_UP_1102/1/Medical Research Council/United Kingdom -- R01 DE022969/DE/NIDCR NIH HHS/ -- R01 GM084875/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Mar 27;507(7493):462-70. doi: 10.1038/nature13182.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670764" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Atlases as Topic ; Cell Line ; Cells, Cultured ; Cluster Analysis ; Conserved Sequence/genetics ; Gene Expression Regulation/genetics ; Gene Regulatory Networks/genetics ; Genes, Essential/genetics ; Genome/genetics ; Humans ; Mice ; *Molecular Sequence Annotation ; Open Reading Frames/genetics ; Organ Specificity ; Promoter Regions, Genetic/*genetics ; RNA, Messenger/analysis/genetics ; Transcription Factors/metabolism ; Transcription Initiation Site ; Transcription, Genetic/genetics ; Transcriptome/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2007-10-13
    Description: Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wood, Laura D -- Parsons, D Williams -- Jones, Sian -- Lin, Jimmy -- Sjoblom, Tobias -- Leary, Rebecca J -- Shen, Dong -- Boca, Simina M -- Barber, Thomas -- Ptak, Janine -- Silliman, Natalie -- Szabo, Steve -- Dezso, Zoltan -- Ustyanksky, Vadim -- Nikolskaya, Tatiana -- Nikolsky, Yuri -- Karchin, Rachel -- Wilson, Paul A -- Kaminker, Joshua S -- Zhang, Zemin -- Croshaw, Randal -- Willis, Joseph -- Dawson, Dawn -- Shipitsin, Michail -- Willson, James K V -- Sukumar, Saraswati -- Polyak, Kornelia -- Park, Ben Ho -- Pethiyagoda, Charit L -- Pant, P V Krishna -- Ballinger, Dennis G -- Sparks, Andrew B -- Hartigan, James -- Smith, Douglas R -- Suh, Erick -- Papadopoulos, Nickolas -- Buckhaults, Phillip -- Markowitz, Sanford D -- Parmigiani, Giovanni -- Kinzler, Kenneth W -- Velculescu, Victor E -- Vogelstein, Bert -- CA 43460/CA/NCI NIH HHS/ -- CA 57345/CA/NCI NIH HHS/ -- CA109274/CA/NCI NIH HHS/ -- CA112828/CA/NCI NIH HHS/ -- CA121113/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- GM070219/GM/NIGMS NIH HHS/ -- GM07309/GM/NIGMS NIH HHS/ -- P30-CA43703/CA/NCI NIH HHS/ -- RR017698/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2007 Nov 16;318(5853):1108-13. Epub 2007 Oct 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17932254" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/metabolism ; Cell Line ; Chromosome Mapping ; Colorectal Neoplasms/*genetics/metabolism ; Computational Biology ; DNA, Neoplasm ; Databases, Genetic ; Genes, Neoplasm ; Genome, Human ; Humans ; Metabolic Networks and Pathways/genetics ; Mice ; Mutation ; Neoplasm Proteins/genetics/metabolism ; Sequence Analysis, DNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2010-06-18
    Description: Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900412/" 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/PMC2900412/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Surolia, Ira -- Pirnie, Stephan P -- Chellappa, Vasant -- Taylor, Kendra N -- Cariappa, Annaiah -- Moya, Jesse -- Liu, Haoyuan -- Bell, Daphne W -- Driscoll, David R -- Diederichs, Sven -- Haider, Khaleda -- Netravali, Ilka -- Le, Sheila -- Elia, Roberto -- Dow, Ethan -- Lee, Annette -- Freudenberg, Jan -- De Jager, Philip L -- Chretien, Yves -- Varki, Ajit -- MacDonald, Marcy E -- Gillis, Tammy -- Behrens, Timothy W -- Bloch, Donald -- Collier, Deborah -- Korzenik, Joshua -- Podolsky, Daniel K -- Hafler, David -- Murali, Mandakolathur -- Sands, Bruce -- Stone, John H -- Gregersen, Peter K -- Pillai, Shiv -- AI 064930/AI/NIAID NIH HHS/ -- AI 068759/AI/NIAID NIH HHS/ -- AI 076505/AI/NIAID NIH HHS/ -- AR 022263/AR/NIAMS NIH HHS/ -- AR 044422/AR/NIAMS NIH HHS/ -- AR 058481/AR/NIAMS NIH HHS/ -- NS 32765/NS/NINDS NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI064930/AI/NIAID NIH HHS/ -- R01 AI064930-04/AI/NIAID NIH HHS/ -- R01 AI068759/AI/NIAID NIH HHS/ -- R01 AI068759-05/AI/NIAID NIH HHS/ -- R01 AI076505/AI/NIAID NIH HHS/ -- R01 AI076505-02/AI/NIAID NIH HHS/ -- R01 AR044422/AR/NIAMS NIH HHS/ -- R01 AR044422-13/AR/NIAMS NIH HHS/ -- RC1 AR058481/AR/NIAMS NIH HHS/ -- RC1 AR058481-01/AR/NIAMS NIH HHS/ -- England -- Nature. 2010 Jul 8;466(7303):243-7. doi: 10.1038/nature09115. Epub 2010 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20555325" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acetylesterase/*genetics/metabolism/secretion ; Alleles ; Animals ; Antibodies, Antinuclear/blood ; Arthritis, Rheumatoid/enzymology/genetics ; Autoimmune Diseases/*enzymology/*genetics ; Autoimmunity/*genetics ; B-Lymphocytes/metabolism ; Biocatalysis ; Carboxylic Ester Hydrolases/*genetics/metabolism/secretion ; Case-Control Studies ; Cell Line ; Diabetes Mellitus, Type 1/enzymology/genetics ; Europe/ethnology ; Exons/genetics ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/*genetics ; Humans ; Mice ; N-Acetylneuraminic Acid/*metabolism ; Odds Ratio ; Polymorphism, Single Nucleotide/genetics ; Sample Size ; Sequence Analysis, DNA
    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: 2013-09-03
    Description: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" 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/PMC3933266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mangravite, Lara M -- Engelhardt, Barbara E -- Medina, Marisa W -- Smith, Joshua D -- Brown, Christopher D -- Chasman, Daniel I -- Mecham, Brigham H -- Howie, Bryan -- Shim, Heejung -- Naidoo, Devesh -- Feng, QiPing -- Rieder, Mark J -- Chen, Yii-Der I -- Rotter, Jerome I -- Ridker, Paul M -- Hopewell, Jemma C -- Parish, Sarah -- Armitage, Jane -- Collins, Rory -- Wilke, Russell A -- Nickerson, Deborah A -- Stephens, Matthew -- Krauss, Ronald M -- HG002585/HG/NHGRI NIH HHS/ -- K99/R00HG006265/HG/NHGRI NIH HHS/ -- MC_U137686853/Medical Research Council/United Kingdom -- P30 DK063491/DK/NIDDK NIH HHS/ -- R00 HG006265/HG/NHGRI NIH HHS/ -- R01 HG002585/HG/NHGRI NIH HHS/ -- R01 HL104133/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL69757/HL/NHLBI NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Oct 17;502(7471):377-80. doi: 10.1038/nature12508. Epub 2013 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sage Bionetworks, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. lara.mangravite@sagebase.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995691" target="_blank"〉PubMed〈/a〉
    Keywords: Amidinotransferases/deficiency/*genetics/metabolism ; Cell Line ; Cholesterol/deficiency/metabolism/pharmacology ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacology ; Lymphocytes/cytology/drug effects/metabolism ; Muscular Diseases/*chemically induced/genetics/metabolism ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/*genetics ; Simvastatin/*adverse effects/pharmacology ; Sterol Regulatory Element Binding Proteins/metabolism ; Transcription, Genetic/drug effects
    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: 2014-08-29
    Description: Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227084/" 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/PMC4227084/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ho, Joshua W K -- Jung, Youngsook L -- Liu, Tao -- Alver, Burak H -- Lee, Soohyun -- Ikegami, Kohta -- Sohn, Kyung-Ah -- Minoda, Aki -- Tolstorukov, Michael Y -- Appert, Alex -- Parker, Stephen C J -- Gu, Tingting -- Kundaje, Anshul -- Riddle, Nicole C -- Bishop, Eric -- Egelhofer, Thea A -- Hu, Sheng'en Shawn -- Alekseyenko, Artyom A -- Rechtsteiner, Andreas -- Asker, Dalal -- Belsky, Jason A -- Bowman, Sarah K -- Chen, Q Brent -- Chen, Ron A-J -- Day, Daniel S -- Dong, Yan -- Dose, Andrea C -- Duan, Xikun -- Epstein, Charles B -- Ercan, Sevinc -- Feingold, Elise A -- Ferrari, Francesco -- Garrigues, Jacob M -- Gehlenborg, Nils -- Good, Peter J -- Haseley, Psalm -- He, Daniel -- Herrmann, Moritz -- Hoffman, Michael M -- Jeffers, Tess E -- Kharchenko, Peter V -- Kolasinska-Zwierz, Paulina -- Kotwaliwale, Chitra V -- Kumar, Nischay -- Langley, Sasha A -- Larschan, Erica N -- Latorre, Isabel -- Libbrecht, Maxwell W -- Lin, Xueqiu -- Park, Richard -- Pazin, Michael J -- Pham, Hoang N -- Plachetka, Annette -- Qin, Bo -- Schwartz, Yuri B -- Shoresh, Noam -- Stempor, Przemyslaw -- Vielle, Anne -- Wang, Chengyang -- Whittle, Christina M -- Xue, Huiling -- Kingston, Robert E -- Kim, Ju Han -- Bernstein, Bradley E -- Dernburg, Abby F -- Pirrotta, Vincenzo -- Kuroda, Mitzi I -- Noble, William S -- Tullius, Thomas D -- Kellis, Manolis -- MacAlpine, David M -- Strome, Susan -- Elgin, Sarah C R -- Liu, Xiaole Shirley -- Lieb, Jason D -- Ahringer, Julie -- Karpen, Gary H -- Park, Peter J -- 092096/Wellcome Trust/United Kingdom -- 101863/Wellcome Trust/United Kingdom -- 54523/Wellcome Trust/United Kingdom -- 5RL9EB008539/EB/NIBIB NIH HHS/ -- K99 HG006259/HG/NHGRI NIH HHS/ -- K99HG006259/HG/NHGRI NIH HHS/ -- R01 GM098461/GM/NIGMS NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R37 GM048405/GM/NIGMS NIH HHS/ -- T32 GM071340/GM/NIGMS NIH HHS/ -- T32 HG002295/HG/NHGRI NIH HHS/ -- U01 HG004258/HG/NHGRI NIH HHS/ -- U01 HG004270/HG/NHGRI NIH HHS/ -- U01 HG004279/HG/NHGRI NIH HHS/ -- U01 HG004695/HG/NHGRI NIH HHS/ -- U01HG004258/HG/NHGRI NIH HHS/ -- U01HG004270/HG/NHGRI NIH HHS/ -- U01HG004279/HG/NHGRI NIH HHS/ -- U01HG004695/HG/NHGRI NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- U54 HG004570/HG/NHGRI NIH HHS/ -- U54 HG006991/HG/NHGRI NIH HHS/ -- U54CA121852/CA/NCI NIH HHS/ -- U54HG004570/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Aug 28;512(7515):449-52. doi: 10.1038/nature13415.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] [4] Victor Chang Cardiac Research Institute and The University of New South Wales, Sydney, New South Wales 2052, Australia (J.W.K.H.); Department of Biochemistry, University at Buffalo, Buffalo, New York 14203, USA (T.L.); Department of Molecular Biology and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA (K.I., T.E.J.); Department of Human Genetics, University of Chicago, Chicago, Illinois 06037, USA (J.D.L.); Division of Genomic Technologies, Center for Life Science Technologies, RIKEN, Yokohama 230-0045, Japan (A.M.); Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA (A.K.); Department of Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA (N.C.R.). ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3]. ; 1] Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [3] [4] Victor Chang Cardiac Research Institute and The University of New South Wales, Sydney, New South Wales 2052, Australia (J.W.K.H.); Department of Biochemistry, University at Buffalo, Buffalo, New York 14203, USA (T.L.); Department of Molecular Biology and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA (K.I., T.E.J.); Department of Human Genetics, University of Chicago, Chicago, Illinois 06037, USA (J.D.L.); Division of Genomic Technologies, Center for Life Science Technologies, RIKEN, Yokohama 230-0045, Japan (A.M.); Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA (A.K.); Department of Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA (N.C.R.). ; Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Biology and Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2] Victor Chang Cardiac Research Institute and The University of New South Wales, Sydney, New South Wales 2052, Australia (J.W.K.H.); Department of Biochemistry, University at Buffalo, Buffalo, New York 14203, USA (T.L.); Department of Molecular Biology and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA (K.I., T.E.J.); Department of Human Genetics, University of Chicago, Chicago, Illinois 06037, USA (J.D.L.); Division of Genomic Technologies, Center for Life Science Technologies, RIKEN, Yokohama 230-0045, Japan (A.M.); Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA (A.K.); Department of Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA (N.C.R.). ; 1] Department of Information and Computer Engineering, Ajou University, Suwon 443-749, Korea [2] Systems Biomedical Informatics Research Center, College of Medicine, Seoul National University, Seoul 110-799, Korea. ; 1] Department of Genome Dynamics, Life Sciences Division, Lawrence Berkeley National Lab, Berkeley, California 94720, USA [2] Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA [3] Victor Chang Cardiac Research Institute and The University of New South Wales, Sydney, New South Wales 2052, Australia (J.W.K.H.); Department of Biochemistry, University at Buffalo, Buffalo, New York 14203, USA (T.L.); Department of Molecular Biology and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA (K.I., T.E.J.); Department of Human Genetics, University of Chicago, Chicago, Illinois 06037, USA (J.D.L.); Division of Genomic Technologies, Center for Life Science Technologies, RIKEN, Yokohama 230-0045, Japan (A.M.); Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA (A.K.); Department of Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA (N.C.R.). ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; The Gurdon Institute and Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. ; 1] National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA [2] National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Biology, Washington University in St. Louis, St. Louis, Missouri 63130, USA. ; 1] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute, Cambridge, Massachusetts 02141, USA [3] Victor Chang Cardiac Research Institute and The University of New South Wales, Sydney, New South Wales 2052, Australia (J.W.K.H.); Department of Biochemistry, University at Buffalo, Buffalo, New York 14203, USA (T.L.); Department of Molecular Biology and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA (K.I., T.E.J.); Department of Human Genetics, University of Chicago, Chicago, Illinois 06037, USA (J.D.L.); Division of Genomic Technologies, Center for Life Science Technologies, RIKEN, Yokohama 230-0045, Japan (A.M.); Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA (A.K.); Department of Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA (N.C.R.). ; 1] Department of Biology, Washington University in St. Louis, St. Louis, Missouri 63130, USA [2] Victor Chang Cardiac Research Institute and The University of New South Wales, Sydney, New South Wales 2052, Australia (J.W.K.H.); Department of Biochemistry, University at Buffalo, Buffalo, New York 14203, USA (T.L.); Department of Molecular Biology and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA (K.I., T.E.J.); Department of Human Genetics, University of Chicago, Chicago, Illinois 06037, USA (J.D.L.); Division of Genomic Technologies, Center for Life Science Technologies, RIKEN, Yokohama 230-0045, Japan (A.M.); Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA (A.K.); Department of Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA (N.C.R.). ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Program in Bioinformatics, Boston University, Boston, Massachusetts 02215, USA. ; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China. ; 1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA [2] Food Science and Technology Department, Faculty of Agriculture, Alexandria University, 21545 El-Shatby, Alexandria, Egypt. ; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Biology and Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard/MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA. ; Department of Anatomy Physiology and Cell Biology, University of California Davis, Davis, California 95616, USA. ; Broad Institute, Cambridge, Massachusetts 02141, USA. ; 1] Department of Biology and Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2] Department of Biology, Center for Genomics and Systems Biology, New York University, New York, New York 10003, USA. ; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Broad Institute, Cambridge, Massachusetts 02141, USA. ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA. ; Princess Margaret Cancer Centre, Toronto, Ontario M6G 1L7, Canada. ; 1] Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; 1] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute, Cambridge, Massachusetts 02141, USA. ; 1] Department of Genome Dynamics, Life Sciences Division, Lawrence Berkeley National Lab, Berkeley, California 94720, USA [2] Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA. ; Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, Rhode Island 02912, USA. ; Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Genome Dynamics, Life Sciences Division, Lawrence Berkeley National Lab, Berkeley, California 94720, USA [2] Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; 1] Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA [2] Department of Molecular Biology, Umea University, 901 87 Umea, Sweden. ; 1] Systems Biomedical Informatics Research Center, College of Medicine, Seoul National University, Seoul 110-799, Korea [2] Seoul National University Biomedical Informatics, Division of Biomedical Informatics, College of Medicine, Seoul National University, Seoul 110-799, Korea. ; 1] Broad Institute, Cambridge, Massachusetts 02141, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA [3] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA. ; 1] Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA [2] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; 1] Program in Bioinformatics, Boston University, Boston, Massachusetts 02215, USA [2] Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA. ; 1] Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Broad Institute, Cambridge, Massachusetts 02141, USA. ; 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Informatics Program, Children's Hospital, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25164756" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/*cytology/*genetics ; Cell Line ; Centromere/genetics/metabolism ; Chromatin/chemistry/*genetics/*metabolism ; Chromatin Assembly and Disassembly/genetics ; DNA Replication/genetics ; Drosophila melanogaster/*cytology/*genetics ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic ; Heterochromatin/chemistry/genetics/metabolism ; Histones/chemistry/metabolism ; Humans ; Molecular Sequence Annotation ; Nuclear Lamina/metabolism ; Nucleosomes/chemistry/genetics/metabolism ; Promoter Regions, Genetic/genetics ; Species Specificity
    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: 2014-02-21
    Description: Members of the nuclear factor-kappaB (NF-kappaB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kappaB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kappaB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kappaB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kappaB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050669/" 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/PMC4050669/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Matthew -- Mohankumar, Kumarasamypet M -- Punchihewa, Chandanamali -- Weinlich, Ricardo -- Dalton, James D -- Li, Yongjin -- Lee, Ryan -- Tatevossian, Ruth G -- Phoenix, Timothy N -- Thiruvenkatam, Radhika -- White, Elsie -- Tang, Bo -- Orisme, Wilda -- Gupta, Kirti -- Rusch, Michael -- Chen, Xiang -- Li, Yuxin -- Nagahawhatte, Panduka -- Hedlund, Erin -- Finkelstein, David -- Wu, Gang -- Shurtleff, Sheila -- Easton, John -- Boggs, Kristy -- Yergeau, Donald -- Vadodaria, Bhavin -- Mulder, Heather L -- Becksfort, Jared -- Gupta, Pankaj -- Huether, Robert -- Ma, Jing -- Song, Guangchun -- Gajjar, Amar -- Merchant, Thomas -- Boop, Frederick -- Smith, Amy A -- Ding, Li -- Lu, Charles -- Ochoa, Kerri -- Zhao, David -- Fulton, Robert S -- Fulton, Lucinda L -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Green, Douglas R -- Zhang, Jinghui -- Ellison, David W -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):451-5. doi: 10.1038/nature13109. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [3]. ; 1] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA. ; Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; MD Anderson Cancer Center Orlando, Pediatric Hematology/Oncology, 92 West Miller MP 318, Orlando, Florida 32806, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [4] Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553141" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Animals ; Base Sequence ; Brain Neoplasms/genetics/metabolism/pathology ; Cell Line ; Cell Nucleus/metabolism ; *Cell Transformation, Neoplastic/genetics ; Chromosomes, Human, Pair 11/genetics ; Ependymoma/*genetics/*metabolism/pathology ; Female ; Humans ; Mice ; Models, Genetic ; Molecular Sequence Data ; NF-kappa B/genetics/*metabolism ; Neural Stem Cells/metabolism/pathology ; Oncogene Proteins, Fusion/genetics/metabolism ; Phosphoproteins/genetics/metabolism ; Proteins/genetics/*metabolism ; *Signal Transduction ; Transcription Factor RelA/genetics/*metabolism ; Translocation, 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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  • 7
    Publication Date: 2010-06-11
    Description: The generation of reprogrammed induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders holds the promise of increased understanding of the aetiologies of complex diseases and may also facilitate the development of novel therapeutic interventions. We have generated iPSCs from patients with LEOPARD syndrome (an acronym formed from its main features; that is, lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness), an autosomal-dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-mitogen-activated protein kinase signalling diseases, which also includes Noonan syndrome, with pleomorphic effects on several tissues and organ systems. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSCs have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization and preferential localization of NFATC4 in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wild-type iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signalling pathways that may promote the disease phenotype.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885001/" 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/PMC2885001/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carvajal-Vergara, Xonia -- Sevilla, Ana -- D'Souza, Sunita L -- Ang, Yen-Sin -- Schaniel, Christoph -- Lee, Dung-Fang -- Yang, Lei -- Kaplan, Aaron D -- Adler, Eric D -- Rozov, Roye -- Ge, Yongchao -- Cohen, Ninette -- Edelmann, Lisa J -- Chang, Betty -- Waghray, Avinash -- Su, Jie -- Pardo, Sherly -- Lichtenbelt, Klaske D -- Tartaglia, Marco -- Gelb, Bruce D -- Lemischka, Ihor R -- 5R01GM078465/GM/NIGMS NIH HHS/ -- R01 GM078465/GM/NIGMS NIH HHS/ -- R01 GM078465-03/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 10;465(7299):808-12. doi: 10.1038/nature09005.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Gene and Cell Medicine, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. xcarvajal@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535210" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Cell Differentiation ; Cell Line ; Cell Lineage ; Cells, Cultured ; Embryonic Stem Cells/metabolism ; Enzyme Activation ; Female ; Fibroblasts/metabolism/pathology ; Gene Expression Profiling ; Homeodomain Proteins/genetics ; Humans ; Induced Pluripotent Stem Cells/enzymology/metabolism/*pathology ; LEOPARD Syndrome/drug therapy/metabolism/*pathology ; Male ; Mitogen-Activated Protein Kinases/metabolism ; *Models, Biological ; Myocytes, Cardiac/metabolism/pathology ; NFATC Transcription Factors/genetics/metabolism ; Octamer Transcription Factor-3/genetics ; Phosphoproteins/analysis ; Polymerase Chain Reaction ; *Precision Medicine ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/metabolism ; SOXB1 Transcription Factors/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: 2009-04-11
    Description: The nuclear factor kappaB (NF-kappaB) transcription factor regulates cellular stress responses and the immune response to infection. NF-kappaB activation results in oscillations in nuclear NF-kappaB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor-alpha at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-kappaB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-kappaB-dependent gene expression, which supports the idea that oscillation frequency has a functional role.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785900/" 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/PMC2785900/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ashall, Louise -- Horton, Caroline A -- Nelson, David E -- Paszek, Pawel -- Harper, Claire V -- Sillitoe, Kate -- Ryan, Sheila -- Spiller, David G -- Unitt, John F -- Broomhead, David S -- Kell, Douglas B -- Rand, David A -- See, Violaine -- White, Michael R H -- BB/C007158/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/C008219/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/C520471/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/D010748/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E004210/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E012965/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/F005938/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBC0071581/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBC0082191/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBC5204711/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBD0107481/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBF0059381/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0500346/Medical Research Council/United Kingdom -- G0500346(73596)/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2009 Apr 10;324(5924):242-6. doi: 10.1126/science.1164860.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown Street, Liverpool, L69 7ZB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19359585" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Animals ; Cell Line ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Feedback, Physiological ; *Gene Expression ; Humans ; I-kappa B Proteins/metabolism ; Mice ; Models, Biological ; Models, Statistical ; NF-kappa B/*metabolism ; Phosphorylation ; Recombinant Fusion Proteins/metabolism ; Stochastic Processes ; Transcription Factor RelA/*metabolism ; *Transcription, Genetic ; Transfection ; Tumor Necrosis Factor-alpha/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2013-07-19
    Description: Down's syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down's syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body'. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of 'chromosome therapy'.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848249/" 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/PMC3848249/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Jun -- Jing, Yuanchun -- Cost, Gregory J -- Chiang, Jen-Chieh -- Kolpa, Heather J -- Cotton, Allison M -- Carone, Dawn M -- Carone, Benjamin R -- Shivak, David A -- Guschin, Dmitry Y -- Pearl, Jocelynn R -- Rebar, Edward J -- Byron, Meg -- Gregory, Philip D -- Brown, Carolyn J -- Urnov, Fyodor D -- Hall, Lisa L -- Lawrence, Jeanne B -- 1F32CA154086/CA/NCI NIH HHS/ -- 2T32HD007439/HD/NICHD NIH HHS/ -- F32 CA154086/CA/NCI NIH HHS/ -- GM053234/GM/NIGMS NIH HHS/ -- GM085548/GM/NIGMS NIH HHS/ -- GM096400 RC4/GM/NIGMS NIH HHS/ -- MOP-13680/Canadian Institutes of Health Research/Canada -- R01 GM053234/GM/NIGMS NIH HHS/ -- R01 GM085548/GM/NIGMS NIH HHS/ -- RC4 GM096400/GM/NIGMS NIH HHS/ -- T32 HD007439/HD/NICHD NIH HHS/ -- England -- Nature. 2013 Aug 15;500(7462):296-300. doi: 10.1038/nature12394. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863942" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Proliferation ; Chromosomes, Human, Pair 21/*genetics ; DNA Methylation ; *Dosage Compensation, Genetic ; Down Syndrome/*genetics/therapy ; Gene Silencing ; Humans ; Induced Pluripotent Stem Cells ; Male ; Mice ; Mutagenesis, Insertional ; Neurogenesis ; RNA, Long Noncoding/genetics/*metabolism ; Sex Chromatin/genetics ; X Chromosome Inactivation/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2011-11-01
    Description: A full description of the human proteome relies on the challenging task of detecting mature and changing forms of protein molecules in the body. Large-scale proteome analysis has routinely involved digesting intact proteins followed by inferred protein identification using mass spectrometry. This 'bottom-up' process affords a high number of identifications (not always unique to a single gene). However, complications arise from incomplete or ambiguous characterization of alternative splice forms, diverse modifications (for example, acetylation and methylation) and endogenous protein cleavages, especially when combinations of these create complex patterns of intact protein isoforms and species. 'Top-down' interrogation of whole proteins can overcome these problems for individual proteins, but has not been achieved on a proteome scale owing to the lack of intact protein fractionation methods that are well integrated with tandem mass spectrometry. Here we show, using a new four-dimensional separation system, identification of 1,043 gene products from human cells that are dispersed into more than 3,000 protein species created by post-translational modification (PTM), RNA splicing and proteolysis. The overall system produced greater than 20-fold increases in both separation power and proteome coverage, enabling the identification of proteins up to 105 kDa and those with up to 11 transmembrane helices. Many previously undetected isoforms of endogenous human proteins were mapped, including changes in multiply modified species in response to accelerated cellular ageing (senescence) induced by DNA damage. Integrated with the latest version of the Swiss-Prot database, the data provide precise correlations to individual genes and proof-of-concept for large-scale interrogation of whole protein molecules. The technology promises to improve the link between proteomics data and complex phenotypes in basic biology and disease research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237778/" 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/PMC3237778/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tran, John C -- Zamdborg, Leonid -- Ahlf, Dorothy R -- Lee, Ji Eun -- Catherman, Adam D -- Durbin, Kenneth R -- Tipton, Jeremiah D -- Vellaichamy, Adaikkalam -- Kellie, John F -- Li, Mingxi -- Wu, Cong -- Sweet, Steve M M -- Early, Bryan P -- Siuti, Nertila -- LeDuc, Richard D -- Compton, Philip D -- Thomas, Paul M -- Kelleher, Neil L -- F30 DA026672/DA/NIDA NIH HHS/ -- F30 DA026672-03/DA/NIDA NIH HHS/ -- GM 067193-08/GM/NIGMS NIH HHS/ -- P30 DA018310/DA/NIDA NIH HHS/ -- P30 DA018310-06/DA/NIDA NIH HHS/ -- P30DA 018310/DA/NIDA NIH HHS/ -- R01 GM067193/GM/NIGMS NIH HHS/ -- R01 GM067193-08/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Oct 30;480(7376):254-8. doi: 10.1038/nature10575.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22037311" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Cell Aging/genetics ; Cell Line ; DNA Damage ; Databases, Protein ; HMGA1a Protein/analysis ; HMGA1b Protein/analysis ; HeLa Cells ; Humans ; Phenotype ; Protein Isoforms/*analysis/*chemistry ; Protein Processing, Post-Translational ; Proteolysis ; Proteome/*analysis/*chemistry ; Proteomics/instrumentation/*methods
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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