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  • Cell Line  (55)
  • Cell Proliferation  (35)
  • Nature Publishing Group (NPG)  (86)
  • 2010-2014  (86)
  • 2014  (37)
  • 2010  (49)
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  • 2010-2014  (86)
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  • 1
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    A promoter-level mammalian expression atlas (2014)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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  • 2
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    A population-specific HTR2B stop codon predisposes to severe impulsivity (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-12-24
    Description: Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency 〉 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183507/" 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/PMC3183507/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bevilacqua, Laura -- Doly, Stephane -- Kaprio, Jaakko -- Yuan, Qiaoping -- Tikkanen, Roope -- Paunio, Tiina -- Zhou, Zhifeng -- Wedenoja, Juho -- Maroteaux, Luc -- Diaz, Silvina -- Belmer, Arnaud -- Hodgkinson, Colin A -- Dell'osso, Liliana -- Suvisaari, Jaana -- Coccaro, Emil -- Rose, Richard J -- Peltonen, Leena -- Virkkunen, Matti -- Goldman, David -- AA-09203/AA/NIAAA NIH HHS/ -- AA-12502/AA/NIAAA NIH HHS/ -- Z01 AA000301-09/Intramural NIH HHS/ -- Z01 AA000301-10/Intramural NIH HHS/ -- Z99 AA999999/Intramural NIH HHS/ -- England -- Nature. 2010 Dec 23;468(7327):1061-6. doi: 10.1038/nature09629.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179162" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/metabolism ; Case-Control Studies ; Cell Line ; Female ; Finland ; Founder Effect ; Gene Expression Regulation ; Gene Knockout Techniques ; Genotype ; Humans ; Impulsive Behavior/*genetics ; Male ; Mental Disorders/genetics ; Mice ; Mice, 129 Strain ; Mice, Knockout ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Receptor, Serotonin, 5-HT2B/*genetics/*metabolism ; Testosterone/blood/cerebrospinal fluid
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma (2014)
    Nature Publishing Group (NPG)
    Details
    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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  • 4
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    Comprehensive methylome map of lineage commitment from haematopoietic progenitors (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-08-20
    Description: Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956609/" 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/PMC2956609/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ji, Hong -- Ehrlich, Lauren I R -- Seita, Jun -- Murakami, Peter -- Doi, Akiko -- Lindau, Paul -- Lee, Hwajin -- Aryee, Martin J -- Irizarry, Rafael A -- Kim, Kitai -- Rossi, Derrick J -- Inlay, Matthew A -- Serwold, Thomas -- Karsunky, Holger -- Ho, Lena -- Daley, George Q -- Weissman, Irving L -- Feinberg, Andrew P -- CA09151/CA/NCI NIH HHS/ -- F32 AI058521/AI/NIAID NIH HHS/ -- F32 AI058521-02/AI/NIAID NIH HHS/ -- F32AI058521/AI/NIAID NIH HHS/ -- P50 HG003233/HG/NHGRI NIH HHS/ -- P50 HG003233-07/HG/NHGRI NIH HHS/ -- P50 HG003233-08/HG/NHGRI NIH HHS/ -- P50HG003233/HG/NHGRI NIH HHS/ -- R00 AG029760/AG/NIA NIH HHS/ -- R00 AG029760-04/AG/NIA NIH HHS/ -- R00AGO29760/PHS HHS/ -- R01 AI047457/AI/NIAID NIH HHS/ -- R01 AI047457-04/AI/NIAID NIH HHS/ -- R01 AI047457-05/AI/NIAID NIH HHS/ -- R01 AI047458/AI/NIAID NIH HHS/ -- R01 CA086065/CA/NCI NIH HHS/ -- R01 GM083084/GM/NIGMS NIH HHS/ -- R01 GM083084-04/GM/NIGMS NIH HHS/ -- R01AI047457/AI/NIAID NIH HHS/ -- R01AI047458/AI/NIAID NIH HHS/ -- R37 CA054358/CA/NCI NIH HHS/ -- R37 CA054358-18/CA/NCI NIH HHS/ -- R37 CA054358-19/CA/NCI NIH HHS/ -- R37CA053458/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):338-42. doi: 10.1038/nature09367. Epub 2010 Aug 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, 570 Rangos, 725 N. Wolfe St., Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20720541" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; *Cell Lineage/genetics ; CpG Islands/genetics ; *DNA Methylation/genetics ; Epigenesis, Genetic ; Gene Expression Profiling ; Genome/genetics ; *Hematopoiesis/genetics ; Hematopoietic Stem Cells/*cytology/*metabolism ; Lymphocytes/cytology/metabolism ; Metabolome ; Metabolomics ; Mice ; Myeloid Cells/cytology/metabolism ; Pluripotent Stem Cells/cytology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-10-22
    Description: Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055799/" 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/PMC3055799/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Xiaohua -- Chakravarti, Deepavali -- Cho, Min Soon -- Liu, Lingzhi -- Gi, Young Jin -- Lin, Yu-Li -- Leung, Marco L -- El-Naggar, Adel -- Creighton, Chad J -- Suraokar, Milind B -- Wistuba, Ignacio -- Flores, Elsa R -- 01DE019765/DE/NIDCR NIH HHS/ -- CA16672/CA/NCI NIH HHS/ -- P30 CA016672-27/CA/NCI NIH HHS/ -- P50 CA070907/CA/NCI NIH HHS/ -- P50 CA070907-10/CA/NCI NIH HHS/ -- P50 CA091846/CA/NCI NIH HHS/ -- P50 CA091846-10/CA/NCI NIH HHS/ -- P50CA070907/CA/NCI NIH HHS/ -- P50CA091846/CA/NCI NIH HHS/ -- U01 DE019765/DE/NIDCR NIH HHS/ -- U01 DE019765-03/DE/NIDCR NIH HHS/ -- England -- Nature. 2010 Oct 21;467(7318):986-90. doi: 10.1038/nature09459.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20962848" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aging ; Cell Line ; Cell Line, Tumor ; DEAD-box RNA Helicases/biosynthesis/deficiency/genetics/*metabolism ; Endoribonucleases/genetics/*metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor/physiology ; Genomic Instability ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*biosynthesis/genetics/metabolism ; Neoplasm Metastasis/*genetics ; Neoplasms/genetics/pathology/secretion ; Phosphoproteins/deficiency/genetics/*metabolism ; Promoter Regions, Genetic/genetics ; Ribonuclease III/biosynthesis/deficiency/genetics/*metabolism ; Trans-Activators/deficiency/genetics/*metabolism ; Transcription Factors ; Transcriptional Activation ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
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    Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome (2010)
    Nature Publishing Group (NPG)
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    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
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    ABCB5 is a limbal stem cell gene required for corneal development and repair (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-18
    Description: Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63alpha-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246512/" 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/PMC4246512/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ksander, Bruce R -- Kolovou, Paraskevi E -- Wilson, Brian J -- Saab, Karim R -- Guo, Qin -- Ma, Jie -- McGuire, Sean P -- Gregory, Meredith S -- Vincent, William J B -- Perez, Victor L -- Cruz-Guilloty, Fernando -- Kao, Winston W Y -- Call, Mindy K -- Tucker, Budd A -- Zhan, Qian -- Murphy, George F -- Lathrop, Kira L -- Alt, Clemens -- Mortensen, Luke J -- Lin, Charles P -- Zieske, James D -- Frank, Markus H -- Frank, Natasha Y -- DP2 OD007483/OD/NIH HHS/ -- DP2OD007483/OD/NIH HHS/ -- EY08098/EY/NEI NIH HHS/ -- I01 BX000516/BX/BLRD VA/ -- I01 RX000989/RX/RRD VA/ -- K08 NS051349/NS/NINDS NIH HHS/ -- K08NS051349/NS/NINDS NIH HHS/ -- P30 EY014801/EY/NEI NIH HHS/ -- P30EY014801/EY/NEI NIH HHS/ -- P41EB015903/EB/NIBIB NIH HHS/ -- R01 CA113796/CA/NCI NIH HHS/ -- R01 CA138231/CA/NCI NIH HHS/ -- R01 CA158467/CA/NCI NIH HHS/ -- R01 EB017274/EB/NIBIB NIH HHS/ -- R01CA113796/CA/NCI NIH HHS/ -- R01CA138231/CA/NCI NIH HHS/ -- R01CA158467/CA/NCI NIH HHS/ -- R01EY018624/EY/NEI NIH HHS/ -- R01EY021768/EY/NEI NIH HHS/ -- U01HL100402/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 17;511(7509):353-7. doi: 10.1038/nature13426. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA [2]. ; 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA. ; 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA [2] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [3] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. ; Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229, USA. ; Stephen A Wynn Institute for Vision Research, Carver College of Medicine, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242, USA. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Ophthalmology, University of Pittsburgh School of Medicine & Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, Pennsylvania 15213, USA. ; Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA [4]. ; 1] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA [2] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA [4] Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [5].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25030174" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/deficiency/*metabolism ; Animals ; Apoptosis ; Biomarkers/metabolism ; Cell Differentiation ; Cell Proliferation ; Female ; Humans ; Limbus Corneae/*cytology/*physiology ; Male ; Mice ; Mice, Knockout ; Molecular Sequence Data ; P-Glycoprotein/deficiency/*metabolism ; *Regeneration ; Stem Cell Transplantation ; Stem Cells/cytology/*metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; *Wound Healing
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    Vascular endothelial growth factor B controls endothelial fatty acid uptake (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-03-17
    Description: The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagberg, Carolina E -- Falkevall, Annelie -- Wang, Xun -- Larsson, Erik -- Huusko, Jenni -- Nilsson, Ingrid -- van Meeteren, Laurens A -- Samen, Erik -- Lu, Li -- Vanwildemeersch, Maarten -- Klar, Joakim -- Genove, Guillem -- Pietras, Kristian -- Stone-Elander, Sharon -- Claesson-Welsh, Lena -- Yla-Herttuala, Seppo -- Lindahl, Per -- Eriksson, Ulf -- England -- Nature. 2010 Apr 8;464(7290):917-21. doi: 10.1038/nature08945. Epub 2010 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tissue Biology Group, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20228789" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Animals ; Biological Transport ; Cell Line ; Cell Nucleus/genetics ; Cells, Cultured ; Endothelium/cytology/*metabolism ; Fatty Acid Transport Proteins/genetics ; Fatty Acids/*metabolism ; Gene Expression Regulation ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/genetics/metabolism ; Mitochondrial Proteins/genetics/metabolism ; Muscles/metabolism ; Myocardium/metabolism ; Neuropilin-1/genetics/metabolism ; Oligonucleotide Array Sequence Analysis ; Organ Specificity ; Signal Transduction ; Transcription, Genetic ; Vascular Endothelial Growth Factor B/deficiency/genetics/*metabolism ; Vascular Endothelial Growth Factor Receptor-1/metabolism
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    Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia (2014)
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    Publication Date: 2014-12-10
    Description: Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403236/" 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/PMC4403236/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wong, Terrence N -- Ramsingh, Giridharan -- Young, Andrew L -- Miller, Christopher A -- Touma, Waseem -- Welch, John S -- Lamprecht, Tamara L -- Shen, Dong -- Hundal, Jasreet -- Fulton, Robert S -- Heath, Sharon -- Baty, Jack D -- Klco, Jeffery M -- Ding, Li -- Mardis, Elaine R -- Westervelt, Peter -- DiPersio, John F -- Walter, Matthew J -- Graubert, Timothy A -- Ley, Timothy J -- Druley, Todd E -- Link, Daniel C -- Wilson, Richard K -- K08 HL116605/HL/NHLBI NIH HHS/ -- P01 CA101937/CA/NCI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):552-5. doi: 10.1038/nature13968. Epub 2014 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA. ; Department of Medicine, Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, California 90089, USA. ; Department of Pediatrics, Division of Hematology/Oncology, Washington University, St Louis, Missouri 63110, USA. ; The Genome Institute, Washington University, St Louis, Missouri 63110, USA. ; 1] Department of Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA. ; AstraZeneca, Gaithersburg, Maryland 20878, USA. ; Division of Biostatistics, Washington University, St Louis, Missouri 63110, USA. ; Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA. ; 1] The Genome Institute, Washington University, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA [3] Department of Genetics, Washington University, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25487151" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cell Lineage/drug effects/*genetics ; Cell Proliferation ; Clone Cells ; DNA Damage ; Drug Resistance, Neoplasm/drug effects/genetics ; Ethylnitrosourea/pharmacology ; Evolution, Molecular ; Genes, p53/*genetics ; Hematopoietic Stem Cells/cytology/drug effects/metabolism/pathology ; Heterozygote ; Humans ; Leukemia, Myeloid, Acute/*chemically induced/*genetics/pathology ; Mice ; Models, Genetic ; Mutation/drug effects/*genetics
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    Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-03
    Description: The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases. Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058342/" 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/PMC3058342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gan, Boyi -- Hu, Jian -- Jiang, Shan -- Liu, Yingchun -- Sahin, Ergun -- Zhuang, Li -- Fletcher-Sananikone, Eliot -- Colla, Simona -- Wang, Y Alan -- Chin, Lynda -- Depinho, Ronald A -- 01CA141508/CA/NCI NIH HHS/ -- R21 CA135057/CA/NCI NIH HHS/ -- R21 CA135057-01/CA/NCI NIH HHS/ -- R21CA135057/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 2;468(7324):701-4. doi: 10.1038/nature09595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Cell Cycle/*physiology ; Cell Proliferation ; Cell Survival ; *Energy Metabolism ; Female ; Gene Deletion ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/*metabolism/pathology ; *Homeostasis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism/pathology ; Multiprotein Complexes ; Pancytopenia/genetics ; Phenotype ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Proteins/metabolism ; Survival Analysis ; TOR Serine-Threonine Kinases ; Transcription Factors/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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