ALBERT

Description: Studies on pluripotent hematopoietic stem cells (HSCs) have been hindered by lack of a positive marker, comparable to the CD34 marker of hematopoietic progenitor cells (HPCs). In human postnatal hematopoietic tissues, 0.1 to 0.5% of CD34(+) cells expressed vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR). Pluripotent HSCs were restricted to the CD34+KDR+ cell fraction. Conversely, lineage-committed HPCs were in the CD34+KDR- subset. On the basis of limiting dilution analysis, the HSC frequency in the CD34+KDR+ fraction was 20 percent in bone marrow (BM) by mouse xenograft assay and 25 to 42 percent in BM, peripheral blood, and cord blood by 12-week long-term culture (LTC) assay. The latter values rose to 53 to 63 percent in LTC supplemented with VEGF and to greater than 95 percent for the cell subfraction resistant to growth factor starvation. Thus, KDR is a positive functional marker defining stem cells and distinguishing them from progenitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ziegler, B L -- Valtieri, M -- Porada, G A -- De Maria, R -- Muller, R -- Masella, B -- Gabbianelli, M -- Casella, I -- Pelosi, E -- Bock, T -- Zanjani, E D -- Peschle, C -- New York, N.Y. -- Science. 1999 Sep 3;285(5433):1553-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hematology and Oncology, University of Tubingen, Otfried-Muller-Strasse 10, D-72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10477517" target="_blank"〉PubMed〈/a〉

Description: Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637443/" 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/PMC2637443/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Franz-Josef -- Laurent, Louise C -- Kostka, Dennis -- Ulitsky, Igor -- Williams, Roy -- Lu, Christina -- Park, In-Hyun -- Rao, Mahendra S -- Shamir, Ron -- Schwartz, Philip H -- Schmidt, Nils O -- Loring, Jeanne F -- K12 5K12HD000849-20/HD/NICHD NIH HHS/ -- P20 GM075059/GM/NIGMS NIH HHS/ -- P20 GM075059-01/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 18;455(7211):401-5. doi: 10.1038/nature07213. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Regenerative Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. fj.mueller@zip-kiel.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724358" target="_blank"〉PubMed〈/a〉

Description: Although many metazoan enzymes that add or remove specific modifications on histone proteins are essential transcriptional regulators, the functional significance of posttranslational modifications on histone proteins is not well understood. Here, we show in Drosophila that a point mutation in lysine 27 of histone H3 (H3-K27) fails to repress transcription of genes that are normally repressed by Polycomb repressive complex 2 (PRC2), the methyltransferase that modifies H3-K27. Moreover, differentiated H3-K27 mutant cells show homeotic transformations like those seen in PRC2 mutant cells. Taken together, these analyses demonstrate that H3-K27 is the crucial physiological substrate that PRC2 modifies for Polycomb repression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pengelly, Ana Raquel -- Copur, Omer -- Jackle, Herbert -- Herzig, Alf -- Muller, Jurg -- New York, N.Y. -- Science. 2013 Feb 8;339(6120):698-9. doi: 10.1126/science.1231382.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Chromatin and Chromosome Biology Research Group, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393264" target="_blank"〉PubMed〈/a〉

Description: Polar auxin transport controls multiple developmental processes in plants, including the formation of vascular tissue. Mutations affecting the PIN-FORMED (PIN1) gene diminish polar auxin transport in Arabidopsis thaliana inflorescence axes. The AtPIN1gene was found to encode a 67-kilodalton protein with similarity to bacterial and eukaryotic carrier proteins, and the AtPIN1 protein was detected at the basal end of auxin transport-competent cells in vascular tissue. AtPIN1 may act as a transmembrane component of the auxin efflux carrier.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galweiler, L -- Guan, C -- Muller, A -- Wisman, E -- Mendgen, K -- Yephremov, A -- Palme, K -- New York, N.Y. -- Science. 1998 Dec 18;282(5397):2226-30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Delbruck-Laboratorium in der Max-Planck-Gesellschaft, Carl-von-Linne-Weg 10, D-50829 Koln, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9856939" target="_blank"〉PubMed〈/a〉

Description: Heritable epigenetic polymorphisms, such as differential cytosine methylation, can underlie phenotypic variation. Moreover, wild strains of the plant Arabidopsis thaliana differ in many epialleles, and these can influence the expression of nearby genes. However, to understand their role in evolution, it is imperative to ascertain the emergence rate and stability of epialleles, including those that are not due to structural variation. We have compared genome-wide DNA methylation among 10 A. thaliana lines, derived 30 generations ago from a common ancestor. Epimutations at individual positions were easily detected, and close to 30,000 cytosines in each strain were differentially methylated. In contrast, larger regions of contiguous methylation were much more stable, and the frequency of changes was in the same low range as that of DNA mutations. Like individual positions, the same regions were often affected by differential methylation in independent lines, with evidence for recurrent cycles of forward and reverse mutations. Transposable elements and short interfering RNAs have been causally linked to DNA methylation. In agreement, differentially methylated sites were farther from transposable elements and showed less association with short interfering RNA expression than invariant positions. The biased distribution and frequent reversion of epimutations have important implications for the potential contribution of sequence-independent epialleles to plant evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Becker, Claude -- Hagmann, Jorg -- Muller, Jonas -- Koenig, Daniel -- Stegle, Oliver -- Borgwardt, Karsten -- Weigel, Detlef -- England -- Nature. 2011 Sep 20;480(7376):245-9. doi: 10.1038/nature10555.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Max Planck Institute for Developmental Biology, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22057020" target="_blank"〉PubMed〈/a〉

Description: Species diversity can be lost through two different but potentially interacting extinction processes: demographic decline and speciation reversal through introgressive hybridization. To investigate the relative contribution of these processes, we analysed historical and contemporary data of replicate whitefish radiations from 17 pre-alpine European lakes and reconstructed changes in genetic species differentiation through time using historical samples. Here we provide evidence that species diversity evolved in response to ecological opportunity, and that eutrophication, by diminishing this opportunity, has driven extinctions through speciation reversal and demographic decline. Across the radiations, the magnitude of eutrophication explains the pattern of species loss and levels of genetic and functional distinctiveness among remaining species. We argue that extinction by speciation reversal may be more widespread than currently appreciated. Preventing such extinctions will require that conservation efforts not only target existing species but identify and protect the ecological and evolutionary processes that generate and maintain species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vonlanthen, P -- Bittner, D -- Hudson, A G -- Young, K A -- Muller, R -- Lundsgaard-Hansen, B -- Roy, D -- Di Piazza, S -- Largiader, C R -- Seehausen, O -- England -- Nature. 2012 Feb 15;482(7385):357-62. doi: 10.1038/nature10824.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Aquatic Ecology and Evolution, Institute of Ecology and Evolution, University of Bern, Baltzerstrasse 6, CH-3012 Bern, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22337055" target="_blank"〉PubMed〈/a〉

Description: Recent advances in DNA synthesis technology have enabled the construction of novel genetic pathways and genomic elements, furthering our understanding of system-level phenomena. The ability to synthesize large segments of DNA allows the engineering of pathways and genomes according to arbitrary sets of design principles. Here we describe a synthetic yeast genome project, Sc2.0, and the first partially synthetic eukaryotic chromosomes, Saccharomyces cerevisiae chromosome synIXR, and semi-synVIL. We defined three design principles for a synthetic genome as follows: first, it should result in a (near) wild-type phenotype and fitness; second, it should lack destabilizing elements such as tRNA genes or transposons; and third, it should have genetic flexibility to facilitate future studies. The synthetic genome features several systemic modifications complying with the design principles, including an inducible evolution system, SCRaMbLE (synthetic chromosome rearrangement and modification by loxP-mediated evolution). We show the utility of SCRaMbLE as a novel method of combinatorial mutagenesis, capable of generating complex genotypes and a broad variety of phenotypes. When complete, the fully synthetic genome will allow massive restructuring of the yeast genome, and may open the door to a new type of combinatorial genetics based entirely on variations in gene content and copy number.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774833/" 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/PMC3774833/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dymond, Jessica S -- Richardson, Sarah M -- Coombes, Candice E -- Babatz, Timothy -- Muller, Heloise -- Annaluru, Narayana -- Blake, William J -- Schwerzmann, Joy W -- Dai, Junbiao -- Lindstrom, Derek L -- Boeke, Annabel C -- Gottschling, Daniel E -- Chandrasegaran, Srinivasan -- Bader, Joel S -- Boeke, Jef D -- AG023779/AG/NIA NIH HHS/ -- R01 AG023779/AG/NIA NIH HHS/ -- R37 AG023779/AG/NIA NIH HHS/ -- England -- Nature. 2011 Sep 14;477(7365):471-6. doi: 10.1038/nature10403.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉High Throughput Biology Center, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21918511" target="_blank"〉PubMed〈/a〉

Description: There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-alpha and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746493/" 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/PMC3746493/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinewietfeld, Markus -- Manzel, Arndt -- Titze, Jens -- Kvakan, Heda -- Yosef, Nir -- Linker, Ralf A -- Muller, Dominik N -- Hafler, David A -- NS2427/NS/NINDS NIH HHS/ -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI045757/AI/NIAID NIH HHS/ -- R01 AI091568/AI/NIAID NIH HHS/ -- R01 NS024247/NS/NINDS NIH HHS/ -- U01 AI102011/AI/NIAID NIH HHS/ -- U19 AI046130/AI/NIAID NIH HHS/ -- U19 AI070352/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):518-22. doi: 10.1038/nature11868. Epub 2013 Mar 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Neurology and Immunobiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA. markus.kleinewietfeld@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23467095" target="_blank"〉PubMed〈/a〉

Description: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P 〈 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955183/" 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/PMC2955183/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lango Allen, Hana -- Estrada, Karol -- Lettre, Guillaume -- Berndt, Sonja I -- Weedon, Michael N -- Rivadeneira, Fernando -- Willer, Cristen J -- Jackson, Anne U -- Vedantam, Sailaja -- Raychaudhuri, Soumya -- Ferreira, Teresa -- Wood, Andrew R -- Weyant, Robert J -- Segre, Ayellet V -- Speliotes, Elizabeth K -- Wheeler, Eleanor -- Soranzo, Nicole -- Park, Ju-Hyun -- Yang, Jian -- Gudbjartsson, Daniel -- Heard-Costa, Nancy L -- Randall, Joshua C -- Qi, Lu -- Vernon Smith, Albert -- Magi, Reedik -- Pastinen, Tomi -- Liang, Liming -- Heid, Iris M -- Luan, Jian'an -- Thorleifsson, Gudmar -- Winkler, Thomas W -- Goddard, Michael E -- Sin Lo, Ken -- Palmer, Cameron -- Workalemahu, Tsegaselassie -- Aulchenko, Yurii S -- Johansson, Asa -- Zillikens, M Carola -- Feitosa, Mary F -- Esko, Tonu -- Johnson, Toby -- Ketkar, Shamika -- Kraft, Peter -- Mangino, Massimo -- Prokopenko, Inga -- Absher, Devin -- Albrecht, Eva -- Ernst, Florian -- Glazer, Nicole L -- Hayward, Caroline -- Hottenga, Jouke-Jan -- Jacobs, Kevin B -- Knowles, Joshua W -- Kutalik, Zoltan -- Monda, Keri L -- Polasek, Ozren -- Preuss, Michael -- Rayner, Nigel W -- Robertson, Neil R -- Steinthorsdottir, Valgerdur -- Tyrer, Jonathan P -- Voight, Benjamin F -- Wiklund, Fredrik -- Xu, Jianfeng -- Zhao, Jing Hua -- Nyholt, Dale R -- Pellikka, Niina -- Perola, Markus -- Perry, John R B -- Surakka, Ida -- Tammesoo, Mari-Liis -- Altmaier, Elizabeth L -- Amin, Najaf -- Aspelund, Thor -- Bhangale, Tushar -- Boucher, Gabrielle -- Chasman, Daniel I -- Chen, Constance -- Coin, Lachlan -- Cooper, Matthew N -- Dixon, Anna L -- Gibson, Quince -- Grundberg, Elin -- Hao, Ke -- Juhani Junttila, M -- Kaplan, Lee M -- Kettunen, Johannes -- Konig, Inke R -- Kwan, Tony -- Lawrence, Robert W -- Levinson, Douglas F -- Lorentzon, Mattias -- McKnight, Barbara -- Morris, Andrew P -- Muller, Martina -- Suh Ngwa, Julius -- Purcell, Shaun -- Rafelt, Suzanne -- Salem, Rany M -- Salvi, Erika -- Sanna, Serena -- Shi, Jianxin -- Sovio, Ulla -- Thompson, John R -- Turchin, Michael C -- Vandenput, Liesbeth -- Verlaan, Dominique J -- Vitart, Veronique -- White, Charles C -- Ziegler, Andreas -- Almgren, Peter -- Balmforth, Anthony J -- Campbell, Harry -- Citterio, Lorena -- De Grandi, Alessandro -- Dominiczak, Anna -- Duan, Jubao -- Elliott, Paul -- Elosua, Roberto -- Eriksson, Johan G -- Freimer, Nelson B -- Geus, Eco J C -- Glorioso, Nicola -- Haiqing, Shen -- Hartikainen, Anna-Liisa -- Havulinna, Aki S -- Hicks, Andrew A -- Hui, Jennie -- Igl, Wilmar -- Illig, Thomas -- Jula, Antti -- Kajantie, Eero -- Kilpelainen, Tuomas O -- Koiranen, Markku -- Kolcic, Ivana -- Koskinen, Seppo -- Kovacs, Peter -- Laitinen, Jaana -- Liu, Jianjun -- Lokki, Marja-Liisa -- Marusic, Ana -- Maschio, Andrea -- Meitinger, Thomas -- Mulas, Antonella -- Pare, Guillaume -- Parker, Alex N -- Peden, John F -- Petersmann, Astrid -- Pichler, Irene -- Pietilainen, Kirsi H -- Pouta, Anneli -- Ridderstrale, Martin -- Rotter, Jerome I -- Sambrook, Jennifer G -- Sanders, Alan R -- Schmidt, Carsten Oliver -- Sinisalo, Juha -- Smit, Jan H -- Stringham, Heather M -- Bragi Walters, G -- Widen, Elisabeth -- Wild, Sarah H -- Willemsen, Gonneke -- Zagato, Laura -- Zgaga, Lina -- Zitting, Paavo -- Alavere, Helene -- Farrall, Martin -- McArdle, Wendy L -- Nelis, Mari -- Peters, Marjolein J -- Ripatti, Samuli -- van Meurs, Joyce B J -- Aben, Katja K -- Ardlie, Kristin G -- Beckmann, Jacques S -- Beilby, John P -- Bergman, Richard N -- Bergmann, Sven -- Collins, Francis S -- Cusi, Daniele -- den Heijer, Martin -- Eiriksdottir, Gudny -- Gejman, Pablo V -- Hall, Alistair S -- Hamsten, Anders -- Huikuri, Heikki V -- Iribarren, Carlos -- Kahonen, Mika -- Kaprio, Jaakko -- Kathiresan, Sekar -- Kiemeney, Lambertus -- Kocher, Thomas -- Launer, Lenore J -- Lehtimaki, Terho -- Melander, Olle -- Mosley, Tom H Jr -- Musk, Arthur W -- Nieminen, Markku S -- O'Donnell, Christopher J -- Ohlsson, Claes -- Oostra, Ben -- Palmer, Lyle J -- Raitakari, Olli -- Ridker, Paul M -- Rioux, John D -- Rissanen, Aila -- Rivolta, Carlo -- Schunkert, Heribert -- Shuldiner, Alan R -- Siscovick, David S -- Stumvoll, Michael -- Tonjes, Anke -- Tuomilehto, Jaakko -- van Ommen, Gert-Jan -- Viikari, Jorma -- Heath, Andrew C -- Martin, Nicholas G -- Montgomery, Grant W -- Province, Michael A -- Kayser, Manfred -- Arnold, Alice M -- Atwood, Larry D -- Boerwinkle, Eric -- Chanock, Stephen J -- Deloukas, Panos -- Gieger, Christian -- Gronberg, Henrik -- Hall, Per -- Hattersley, Andrew T -- Hengstenberg, Christian -- Hoffman, Wolfgang -- Lathrop, G Mark -- Salomaa, Veikko -- Schreiber, Stefan -- Uda, Manuela -- Waterworth, Dawn -- Wright, Alan F -- Assimes, Themistocles L -- Barroso, Ines -- Hofman, Albert -- Mohlke, Karen L -- Boomsma, Dorret I -- Caulfield, Mark J -- Cupples, L Adrienne -- Erdmann, Jeanette -- Fox, Caroline S -- Gudnason, Vilmundur -- Gyllensten, Ulf -- Harris, Tamara B -- Hayes, Richard B -- Jarvelin, Marjo-Riitta -- Mooser, Vincent -- Munroe, Patricia B -- Ouwehand, Willem H -- Penninx, Brenda W -- Pramstaller, Peter P -- Quertermous, Thomas -- Rudan, Igor -- Samani, Nilesh J -- Spector, Timothy D -- Volzke, Henry -- Watkins, Hugh -- Wilson, James F -- Groop, Leif C -- Haritunians, Talin -- Hu, Frank B -- Kaplan, Robert C -- Metspalu, Andres -- North, Kari E -- Schlessinger, David -- Wareham, Nicholas J -- Hunter, David J -- O'Connell, Jeffrey R -- Strachan, David P -- Wichmann, H-Erich -- Borecki, Ingrid B -- van Duijn, Cornelia M -- Schadt, Eric E -- Thorsteinsdottir, Unnur -- Peltonen, Leena -- Uitterlinden, Andre G -- Visscher, Peter M -- Chatterjee, Nilanjan -- Loos, Ruth J F -- Boehnke, Michael -- McCarthy, Mark I -- Ingelsson, Erik -- Lindgren, Cecilia M -- Abecasis, Goncalo R -- Stefansson, Kari -- Frayling, Timothy M -- Hirschhorn, Joel N -- 064890/Wellcome Trust/United Kingdom -- 068545/Wellcome Trust/United Kingdom -- 068545/Z/02/Wellcome Trust/United Kingdom -- 072856/Wellcome Trust/United Kingdom -- 072960/Wellcome Trust/United Kingdom -- 075491/Wellcome Trust/United Kingdom -- 076113/Wellcome Trust/United Kingdom -- 076113/B/04/Z/Wellcome Trust/United Kingdom -- 076113/C/04/Z/Wellcome Trust/United Kingdom -- 077016/Wellcome Trust/United Kingdom -- 077016/Z/05/Z/Wellcome Trust/United Kingdom -- 079557/Wellcome Trust/United Kingdom -- 079771/Wellcome Trust/United Kingdom -- 079895/Wellcome Trust/United Kingdom -- 081682/Wellcome Trust/United Kingdom -- 081682/Z/06/Z/Wellcome Trust/United Kingdom -- 083270/Wellcome Trust/United Kingdom -- 084183/Z/07/Z/Wellcome Trust/United Kingdom -- 085301/Wellcome Trust/United Kingdom -- 085301/Z/08/Z/Wellcome Trust/United Kingdom -- 086596/Wellcome Trust/United Kingdom -- 086596/Z/08/Z/Wellcome Trust/United Kingdom -- 088885/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 091746/Wellcome Trust/United Kingdom -- 091746/Z/10/Z/Wellcome Trust/United Kingdom -- 263-MA-410953/PHS HHS/ -- AA014041/AA/NIAAA NIH HHS/ -- AA07535/AA/NIAAA NIH HHS/ -- AA10248/AA/NIAAA NIH HHS/ -- AA13320/AA/NIAAA NIH HHS/ -- AA13321/AA/NIAAA NIH HHS/ -- AA13326/AA/NIAAA NIH HHS/ -- CA047988/CA/NCI NIH HHS/ -- CA49449/CA/NCI NIH HHS/ -- CA50385/CA/NCI NIH HHS/ -- CA65725/CA/NCI NIH HHS/ -- CA67262/CA/NCI NIH HHS/ -- CA87969/CA/NCI NIH HHS/ -- CZB/4/276/Chief Scientist Office/United Kingdom -- CZB/4/279/Chief Scientist Office/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- DA12854/DA/NIDA NIH HHS/ -- DK062370/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK072193/DK/NIDDK NIH HHS/ -- DK079466/DK/NIDDK NIH HHS/ -- DK080145/DK/NIDDK NIH HHS/ -- DK46200/DK/NIDDK NIH HHS/ -- DK58845/DK/NIDDK NIH HHS/ -- F32 DK079466/DK/NIDDK NIH HHS/ -- F32 DK079466-01/DK/NIDDK NIH HHS/ -- G0000649/Medical Research Council/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0500539/Medical Research Council/United Kingdom -- G0600331/Medical Research Council/United Kingdom -- G0600331(77796)/Medical Research Council/United Kingdom -- G0601261/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9521010(63660)/Medical Research Council/United Kingdom -- G9521010D/Medical Research Council/United Kingdom -- HG002651/HG/NHGRI NIH HHS/ -- HG005214/HG/NHGRI NIH HHS/ 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GM074518-05/GM/NIGMS NIH HHS/ -- U01 HG004399/HG/NHGRI NIH HHS/ -- U01 HG004399-02/HG/NHGRI NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HG004402-02/HG/NHGRI NIH HHS/ -- U01 HG005214/HG/NHGRI NIH HHS/ -- U01 HG005214-02/HG/NHGRI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL069757-10/HL/NHLBI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL072515-06/HL/NHLBI NIH HHS/ -- U01 HL080295/HL/NHLBI NIH HHS/ -- U01 HL080295-04/HL/NHLBI NIH HHS/ -- U01 HL084729/HL/NHLBI NIH HHS/ -- U01 HL084729-03/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U01 HL084756-03/HL/NHLBI NIH HHS/ -- U01 MH079469/MH/NIMH NIH HHS/ -- U01 MH079469-03/MH/NIMH NIH HHS/ -- U01 MH079470/MH/NIMH NIH HHS/ -- U01 MH079470-03/MH/NIMH NIH HHS/ -- U01-CA098233/CA/NCI NIH HHS/ -- U01-GM074518/GM/NIGMS NIH HHS/ -- U01-HG004399/HG/NHGRI NIH HHS/ -- U01-HG004402/HG/NHGRI NIH HHS/ -- U01-HL080295/HL/NHLBI NIH HHS/ -- U01-HL084756/HL/NHLBI NIH HHS/ -- U01-HL72515/HL/NHLBI NIH HHS/ -- U01-MH79469/MH/NIMH NIH HHS/ -- U01-MH79470/MH/NIMH NIH HHS/ -- U54-RR020278/RR/NCRR NIH HHS/ -- UL1-RR025005/RR/NCRR NIH HHS/ -- Z01-AG00675/AG/NIA NIH HHS/ -- Z01-AG007380/AG/NIA NIH HHS/ -- Z01-HG000024/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2010 Oct 14;467(7317):832-8. doi: 10.1038/nature09410. Epub 2010 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX1 2LU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881960" target="_blank"〉PubMed〈/a〉

Description: An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2(+) neural progenitors, Dcx(+) newborn neurons, and Olig2(+) oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057569/" 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/PMC3057569/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jaskelioff, Mariela -- Muller, Florian L -- Paik, Ji-Hye -- Thomas, Emily -- Jiang, Shan -- Adams, Andrew C -- Sahin, Ergun -- Kost-Alimova, Maria -- Protopopov, Alexei -- Cadinanos, Juan -- Horner, James W -- Maratos-Flier, Eleftheria -- Depinho, Ronald A -- R01 CA084628/CA/NCI NIH HHS/ -- R01 CA084628-19/CA/NCI NIH HHS/ -- R01CA84628/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- U01CA141508/CA/NCI NIH HHS/ -- England -- Nature. 2011 Jan 6;469(7328):102-6. doi: 10.1038/nature09603. Epub 2010 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21113150" target="_blank"〉PubMed〈/a〉