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  • 1
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    Sequential cancer mutations in cultured human intestinal stem cells (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-04-30
    Description: Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Drost, Jarno -- van Jaarsveld, Richard H -- Ponsioen, Bas -- Zimberlin, Cheryl -- van Boxtel, Ruben -- Buijs, Arjan -- Sachs, Norman -- Overmeer, Rene M -- Offerhaus, G Johan -- Begthel, Harry -- Korving, Jeroen -- van de Wetering, Marc -- Schwank, Gerald -- Logtenberg, Meike -- Cuppen, Edwin -- Snippert, Hugo J -- Medema, Jan Paul -- Kops, Geert J P L -- Clevers, Hans -- England -- Nature. 2015 May 7;521(7550):43-7. doi: 10.1038/nature14415. Epub 2015 Apr 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584CT Utrecht, The Netherlands [2] Cancer Genomics Netherlands, UMC Utrecht, 3584CG Utrecht, The Netherlands. ; 1] Cancer Genomics Netherlands, UMC Utrecht, 3584CG Utrecht, The Netherlands [2] Molecular Cancer Research, Centre for Molecular Medicine, UMC Utrecht, 3584CG, Utrecht, The Netherlands. ; 1] Cancer Genomics Netherlands, UMC Utrecht, 3584CG Utrecht, The Netherlands [2] Laboratory of Experimental Oncology and Radiobiology, Centre for Experimental Molecular Medicine, AMC, 1105AZ Amsterdam, The Netherlands. ; Department of Medical Genetics, UMC Utrecht, 3508AB Utrecht, The Netherlands. ; Department of Pathology, UMC Utrecht, 3584CX Utrecht, The Netherlands. ; 1] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584CT Utrecht, The Netherlands [2] Cancer Genomics Netherlands, UMC Utrecht, 3584CG Utrecht, The Netherlands [3] Foundation Hubrecht Organoid Technology (HUB), 3584CT Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25924068" target="_blank"〉PubMed〈/a〉
    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 systematic genome-wide analysis of zebrafish protein-coding gene function (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-04-19
    Description: Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743023/" 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/PMC3743023/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kettleborough, Ross N W -- Busch-Nentwich, Elisabeth M -- Harvey, Steven A -- Dooley, Christopher M -- de Bruijn, Ewart -- van Eeden, Freek -- Sealy, Ian -- White, Richard J -- Herd, Colin -- Nijman, Isaac J -- Fenyes, Fruzsina -- Mehroke, Selina -- Scahill, Catherine -- Gibbons, Richard -- Wali, Neha -- Carruthers, Samantha -- Hall, Amanda -- Yen, Jennifer -- Cuppen, Edwin -- Stemple, Derek L -- 098051/Wellcome Trust/United Kingdom -- 5R01HG00481/HG/NHGRI NIH HHS/ -- G0777791/Medical Research Council/United Kingdom -- England -- Nature. 2013 Apr 25;496(7446):494-7. doi: 10.1038/nature11992. Epub 2013 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23594742" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Exome/genetics ; Female ; Gene Knockout Techniques ; Genetic Complementation Test ; Genome/*genetics ; Genomics ; Male ; Molecular Sequence Annotation ; Mutagenesis ; Mutation/genetics ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Zebrafish/*genetics/physiology ; Zebrafish Proteins/*genetics/metabolism
    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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  • 3
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    Genome sequencing of normal cells reveals developmental lineages and mutational processes (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-07-22
    Description: The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree, the number of divisions that each cell has undergone and the mutational processes that have been operative. Here we describe whole genomes of clonal lines derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227286/" 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/PMC4227286/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Behjati, Sam -- Huch, Meritxell -- van Boxtel, Ruben -- Karthaus, Wouter -- Wedge, David C -- Tamuri, Asif U -- Martincorena, Inigo -- Petljak, Mia -- Alexandrov, Ludmil B -- Gundem, Gunes -- Tarpey, Patrick S -- Roerink, Sophie -- Blokker, Joyce -- Maddison, Mark -- Mudie, Laura -- Robinson, Ben -- Nik-Zainal, Serena -- Campbell, Peter -- Goldman, Nick -- van de Wetering, Marc -- Cuppen, Edwin -- Clevers, Hans -- Stratton, Michael R -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 092096/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 104151/Wellcome Trust/United Kingdom -- WT100183MA/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Sep 18;513(7518):422-5. doi: 10.1038/nature13448. Epub 2014 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] Department of Paediatrics, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK. ; 1] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, CancerGenomiCs.nl &University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands [2] [3] Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK. ; 1] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, CancerGenomiCs.nl &University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands [2]. ; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. ; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, CancerGenomiCs.nl &University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043003" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Clocks/genetics ; Cell Division ; Cell Lineage/*genetics ; Cells, Cultured ; Clone Cells/*cytology/*metabolism ; Embryo, Mammalian/cytology ; Genome/*genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mutagenesis/*genetics ; Mutation/*genetics ; Mutation Rate ; Organoids/cytology/metabolism ; Phylogeny ; Sequence Analysis, DNA ; Tail/cytology
    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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  • 4
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    Genome-wide analysis reveals NRP1 as a direct HIF1{alpha}-E2F7 target in the regulation of motorneuron guidance in vivo (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-06
    Description: In this study, we explored the existence of a transcriptional network co-regulated by E2F7 and HIF1α, as we show that expression of E2F7, like HIF1α, is induced in hypoxia, and because of the previously reported ability of E2F7 to interact with HIF1α. Our genome-wide analysis uncovers a transcriptional network that is directly controlled by HIF1α and E2F7, and demonstrates both stimulatory and repressive functions of the HIF1α -E2F7 complex. Among this network we reveal Neuropilin 1 ( NRP1 ) as a HIF1α-E2F7 repressed gene. By performing in vitro and in vivo reporter assays we demonstrate that the HIF1α-E2F7 mediated NRP1 repression depends on a 41 base pairs ‘E2F-binding site hub’, providing a molecular mechanism for a previously unanticipated role for HIF1α in transcriptional repression. To explore the biological significance of this regulation we performed in situ hybridizations and observed enhanced nrp1a expression in spinal motorneurons (MN) of zebrafish embryos, upon morpholino-inhibition of e2f7/8 or hif1α . Consistent with the chemo-repellent role of nrp1a, morpholino-inhibition of e2f7/8 or hif1α caused MN truncations, which was rescued in TALEN-induced nrp1a hu10012 mutants, and phenocopied in e2f7/8 mutant zebrafish. Therefore, we conclude that repression of NRP1 by the HIF1α-E2F7 complex regulates MN axon guidance in vivo .
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Sambamba: fast processing of NGS alignment formats (2015)
    Oxford University Press
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    Publication Date: 2015-06-14
    Description: : Sambamba is a high-performance robust tool and library for working with SAM, BAM and CRAM sequence alignment files; the most common file formats for aligned next generation sequencing data. Sambamba is a faster alternative to samtools that exploits multi-core processing and dramatically reduces processing time. Sambamba is being adopted at sequencing centers, not only because of its speed, but also because of additional functionality, including coverage analysis and powerful filtering capability. Availability and implementation: Sambamba is free and open source software, available under a GPLv2 license. Sambamba can be downloaded and installed from http://www.open-bio.org/wiki/Sambamba . Sambamba v0.5.0 was released with doi:10.5281/zenodo.13200. Contact : j.c.p.prins@umcutrecht.nl
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 6
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    E2F7 represses a network of oscillating cell cycle genes to control S-phase progression (2012)
    Oxford University Press
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    Publication Date: 2012-04-24
    Description: E2F transcription factors are known to be important for timely activation of G 1 /S and G 2 /M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle-regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G 1 /S-regulated genes and represses their transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resembles the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short-term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G 0 -G 1 /S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G 2 /M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 directly controls the downswing of oscillating G 1 /S genes during S-phase progression.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis (2012)
    Oxford University Press
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    Publication Date: 2012-05-11
    Description: Mutations in NIPA1 cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease characterized by an (upper) motor neuron phenotype. Deletions of NIPA1 have been associated with a higher susceptibility to amyotrophic lateral sclerosis (ALS). The exact role of genetic variation in NIPA1 in ALS susceptibility and disease course is, however, not known. We sequenced the entire coding sequence of NIPA1 and genotyped a polyalanine repeat located in the first exon of NIPA1. A total of 2292 ALS patients and 2777 controls from three independent European populations were included. We identified two sequence variants that have a potentially damaging effect on NIPA1 protein function. Both variants were identified in ALS patients; no damaging variants were found in controls. Secondly, we found a significant effect of ‘long’ polyalanine repeat alleles on disease susceptibility: odds ratio = 1.71, P = 1.6 x 10 –4 . Our analyses also revealed a significant effect of ‘long’ alleles on patient survival [hazard ratio (HR) = 1.60, P = 4.2 x 10 –4 ] and on the age at onset of symptoms (HR = 1.37, P = 4.6 x 10 –3 ). In patients carrying ‘long’ alleles, median survival was 3 months shorter than patients with ‘normal’ genotypes and onset of symptoms occurred 3.6 years earlier. Our data show that NIPA1 polyalanine repeat expansions are a common risk factor for ALS and modulate disease course.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer (2017)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2017-10-13
    Description: Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair–deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1 , which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.
    Keywords: Genetics, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 9
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    Genetics of biopsy-derived tumor organoids [Genetics] (2015)
    National Academy of Sciences
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    Publication Date: 2015-10-28
    Description: Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 10
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    Early divergence of mutational processes in human fetal tissues (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉A developing human fetus needs to balance rapid cellular expansion with maintaining genomic stability. Here, we accurately quantified and characterized somatic mutation accumulation in fetal tissues by analyzing individual stem cells from human fetal liver and intestine. Fetal mutation rates were about fivefold higher than in tissue-matched adult stem cells. The mutational landscape of fetal intestinal stem cells resembled that of adult intestinal stem cells, while the mutation spectrum of fetal liver stem cells is distinct from stem cells of the fetal intestine and the adult liver. Our analyses indicate that variation in mutational mechanisms, including oxidative stress and spontaneous deamination of methylated cytosines, contributes to the observed divergence in mutation accumulation patterns and drives genetic mosaicism in humans.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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