ALBERT

Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514/" 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/PMC4201514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Northcott, Paul A -- Lee, Catherine -- Zichner, Thomas -- Stutz, Adrian M -- Erkek, Serap -- Kawauchi, Daisuke -- Shih, David J H -- Hovestadt, Volker -- Zapatka, Marc -- Sturm, Dominik -- Jones, David T W -- Kool, Marcel -- Remke, Marc -- Cavalli, Florence M G -- Zuyderduyn, Scott -- Bader, Gary D -- VandenBerg, Scott -- Esparza, Lourdes Adriana -- Ryzhova, Marina -- Wang, Wei -- Wittmann, Andrea -- Stark, Sebastian -- Sieber, Laura -- Seker-Cin, Huriye -- Linke, Linda -- Kratochwil, Fabian -- Jager, Natalie -- Buchhalter, Ivo -- Imbusch, Charles D -- Zipprich, Gideon -- Raeder, Benjamin -- Schmidt, Sabine -- Diessl, Nicolle -- Wolf, Stephan -- Wiemann, Stefan -- Brors, Benedikt -- Lawerenz, Chris -- Eils, Jurgen -- Warnatz, Hans-Jorg -- Risch, Thomas -- Yaspo, Marie-Laure -- Weber, Ursula D -- Bartholomae, Cynthia C -- von Kalle, Christof -- Turanyi, Eszter -- Hauser, Peter -- Sanden, Emma -- Darabi, Anna -- Siesjo, Peter -- Sterba, Jaroslav -- Zitterbart, Karel -- Sumerauer, David -- van Sluis, Peter -- Versteeg, Rogier -- Volckmann, Richard -- Koster, Jan -- Schuhmann, Martin U -- Ebinger, Martin -- Grimes, H Leighton -- Robinson, Giles W -- Gajjar, Amar -- Mynarek, Martin -- von Hoff, Katja -- Rutkowski, Stefan -- Pietsch, Torsten -- Scheurlen, Wolfram -- Felsberg, Jorg -- Reifenberger, Guido -- Kulozik, Andreas E -- von Deimling, Andreas -- Witt, Olaf -- Eils, Roland -- Gilbertson, Richard J -- Korshunov, Andrey -- Taylor, Michael D -- Lichter, Peter -- Korbel, Jan O -- Wechsler-Reya, Robert J -- Pfister, Stefan M -- 5P30CA030199/CA/NCI NIH HHS/ -- P01 CA096832/CA/NCI NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P41GM103504/GM/NIGMS NIH HHS/ -- R01 CA159859/CA/NCI NIH HHS/ -- England -- Nature. 2014 Jul 24;511(7510):428-34. doi: 10.1038/nature13379. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; 1] Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA [2] Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [3]. ; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2]. ; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada. ; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany. ; Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany. ; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary. ; 2nd Department of Pediatrics, Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary. ; 1] Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden [2] Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden. ; Department of Pediatric Oncology, Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic. ; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Uvalu 84, Prague 150 06, Czech Republic. ; Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands. ; Department of Neurosurgery, Tubingen University Hospital, Hoppe-Seyler Strasse 3, Tubingen 72076, Germany. ; Division of Immunobiology, Program in Cancer Pathology of the Divisions of Experimental Hematology and Pathology, Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA. ; 1] Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2] Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. ; Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany. ; Cnopf'sche Kinderklinik, Nurnberg Children's Hospital, St-Johannis-Muhlgasse 19, Nurnberg 90419, Germany. ; Department of Neuropathology, Heinrich-Heine-University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany. ; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. ; Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany. ; 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [2] Division of Neurosurgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2] EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043047" target="_blank"〉PubMed〈/a〉

Description: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hovestadt, Volker -- Jones, David T W -- Picelli, Simone -- Wang, Wei -- Kool, Marcel -- Northcott, Paul A -- Sultan, Marc -- Stachurski, Katharina -- Ryzhova, Marina -- Warnatz, Hans-Jorg -- Ralser, Meryem -- Brun, Sonja -- Bunt, Jens -- Jager, Natalie -- Kleinheinz, Kortine -- Erkek, Serap -- Weber, Ursula D -- Bartholomae, Cynthia C -- von Kalle, Christof -- Lawerenz, Chris -- Eils, Jurgen -- Koster, Jan -- Versteeg, Rogier -- Milde, Till -- Witt, Olaf -- Schmidt, Sabine -- Wolf, Stephan -- Pietsch, Torsten -- Rutkowski, Stefan -- Scheurlen, Wolfram -- Taylor, Michael D -- Brors, Benedikt -- Felsberg, Jorg -- Reifenberger, Guido -- Borkhardt, Arndt -- Lehrach, Hans -- Wechsler-Reya, Robert J -- Eils, Roland -- Yaspo, Marie-Laure -- Landgraf, Pablo -- Korshunov, Andrey -- Zapatka, Marc -- Radlwimmer, Bernhard -- Pfister, Stefan M -- Lichter, Peter -- England -- Nature. 2014 Jun 26;510(7506):537-41. doi: 10.1038/nature13268. Epub 2014 May 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany. ; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia. ; Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA. ; 1] Queensland Brain Institute, University of Queensland, QBI Building, St Lucia, Queensland 4072, Australia [2] Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany. ; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany. ; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. ; 1] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany [2] Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, Bonn 53105, Germany. ; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. ; Cnopf'sche Kinderklinik, Nurnberg Children's Hospital, St.-Johannis-Muhlgasse 19, Nurnberg 90419, Germany. ; 1] Program in Developmental and Stem Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [2] Division of Neurosurgery, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Neuropathology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany [2] German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Institute of Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Heidelberg 69120, Germany [3] Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg 69120, Germany [4] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 220-221, Heidelberg, 69120 Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847876" target="_blank"〉PubMed〈/a〉

Description: Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404520/" 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/PMC4404520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Radford, Elizabeth J -- Ito, Mitsuteru -- Shi, Hui -- Corish, Jennifer A -- Yamazawa, Kazuki -- Isganaitis, Elvira -- Seisenberger, Stefanie -- Hore, Timothy A -- Reik, Wolf -- Erkek, Serap -- Peters, Antoine H F M -- Patti, Mary-Elizabeth -- Ferguson-Smith, Anne C -- 095606/Wellcome Trust/United Kingdom -- 095645/Wellcome Trust/United Kingdom -- P30 DK036836/DK/NIDDK NIH HHS/ -- P30DK036836/DK/NIDDK NIH HHS/ -- R00 HD064793/HD/NICHD NIH HHS/ -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Aug 15;345(6198):1255903. doi: 10.1126/science.1255903. Epub 2014 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. ; Research Division, Joslin Diabetes Center and Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA. ; The Babraham Institute, Babraham, Cambridge, and Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. ; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland. Swiss Institute of Bioinformatics, Basel, Switzerland. ; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland. ; Research Division, Joslin Diabetes Center and Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA. afsmith@mole.bio.cam.ac.uk mary.elizabeth.patti@joslin.harvard.edu. ; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. afsmith@mole.bio.cam.ac.uk mary.elizabeth.patti@joslin.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25011554" target="_blank"〉PubMed〈/a〉

Description: A father's lifetime experiences can be transmitted to his offspring to affect health and development. However, the mechanisms underlying paternal epigenetic transmission are unclear. Unlike in somatic cells, there are few nucleosomes in sperm, and their function in epigenetic inheritance is unknown. We generated transgenic mice in which overexpression of the histone H3 lysine 4 (H3K4) demethylase KDM1A (also known as LSD1) during spermatogenesis reduced H3K4 dimethylation in sperm. KDM1A overexpression in one generation severely impaired development and survivability of offspring. These defects persisted transgenerationally in the absence of KDM1A germline expression and were associated with altered RNA profiles in sperm and offspring. We show that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing sperm, without changes to DNA methylation at CpG-rich regions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siklenka, Keith -- Erkek, Serap -- Godmann, Maren -- Lambrot, Romain -- McGraw, Serge -- Lafleur, Christine -- Cohen, Tamara -- Xia, Jianguo -- Suderman, Matthew -- Hallett, Michael -- Trasler, Jacquetta -- Peters, Antoine H F M -- Kimmins, Sarah -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):aab2006. doi: 10.1126/science.aab2006. Epub 2015 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. ; Friedrich Miescher Institute for Biomedical Research (FMI), CH-4058 Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland. ; Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada. ; Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. ; Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada. Institute of Parasitology, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada. ; MRC Integrative Epidemiology Unity, School of Social and Community Medicine, University of Bristol, Bristol, UK. ; McGill Centre for Bioinformatics, School of Computer Science, Faculty of Science, McGill University, Montreal, Quebec, Canada. ; Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Department of Human Genetics and Department of Pharmacology and Therapeutics, Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, Quebec, Canada. ; Friedrich Miescher Institute for Biomedical Research (FMI), CH-4058 Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland. sarah.kimmins@mcgill.ca antoine.peters@fmi.ch. ; Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada. sarah.kimmins@mcgill.ca antoine.peters@fmi.ch.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26449473" target="_blank"〉PubMed〈/a〉

Description: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Charles Y -- Erkek, Serap -- Tong, Yiai -- Yin, Linlin -- Federation, Alexander J -- Zapatka, Marc -- Haldipur, Parthiv -- Kawauchi, Daisuke -- Risch, Thomas -- Warnatz, Hans-Jorg -- Worst, Barbara C -- Ju, Bensheng -- Orr, Brent A -- Zeid, Rhamy -- Polaski, Donald R -- Segura-Wang, Maia -- Waszak, Sebastian M -- Jones, David T W -- Kool, Marcel -- Hovestadt, Volker -- Buchhalter, Ivo -- Sieber, Laura -- Johann, Pascal -- Chavez, Lukas -- Groschel, Stefan -- Ryzhova, Marina -- Korshunov, Andrey -- Chen, Wenbiao -- Chizhikov, Victor V -- Millen, Kathleen J -- Amstislavskiy, Vyacheslav -- Lehrach, Hans -- Yaspo, Marie-Laure -- Eils, Roland -- Lichter, Peter -- Korbel, Jan O -- Pfister, Stefan M -- Bradner, James E -- Northcott, Paul A -- England -- Nature. 2016 Feb 4;530(7588):57-62. doi: 10.1038/nature16546. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA. ; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Bone Marrow Transplantation &Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Oncology, NCT Heidelberg, 69120 Heidelberg, Germany. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 125047 Moscow, Russia. ; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, 69120 Heidelberg, Germany. ; Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA. ; Department of Pediatrics, Genetics Division, University of Washington, Seattle, Washington 98195, USA. ; Institute of Pharmacy and Molecular Biotechnology and BioQuant, University of Heidelberg, 69117 Heidelberg, Germany. ; Department of Pediatrics, University of Heidelberg, 69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814967" target="_blank"〉PubMed〈/a〉