Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Publication Date: 2016-04-21
    Description: Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWAS-identified variants in regulatory DNA elements of disease-relevant cell types. Furthermore, single nucleotide polymorphism (SNP)-specific changes in transcription factor binding are correlated with heritable alterations in chromatin state and considered a major mediator of sequence-dependent regulation of gene expression. Here we describe a novel strategy to functionally dissect the cis-acting effect of genetic risk variants in regulatory elements on gene expression by combining genome-wide epigenetic information with clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9 genome editing in human pluripotent stem cells. By generating a genetically precisely controlled experimental system, we identify a common Parkinson's disease associated risk variant in a non-coding distal enhancer element that regulates the expression of alpha-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson's disease. Our data suggest that the transcriptional deregulation of SNCA is associated with sequence-dependent binding of the brain-specific transcription factors EMX2 and NKX6-1. This work establishes an experimental paradigm to functionally connect genetic variation with disease-relevant phenotypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soldner, Frank -- Stelzer, Yonatan -- Shivalila, Chikdu S -- Abraham, Brian J -- Latourelle, Jeanne C -- Barrasa, M Inmaculada -- Goldmann, Johanna -- Myers, Richard H -- Young, Richard A -- Jaenisch, Rudolf -- 1R01NS088538-01/NS/NINDS NIH HHS/ -- 2R01MH104610-15/MH/NIMH NIH HHS/ -- R01 NS088538/NS/NINDS NIH HHS/ -- England -- Nature. 2016 May 5;533(7601):95-9. doi: 10.1038/nature17939. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Whitehead Institute, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, Massachusetts 02139, USA. ; Department of Neurology, Boston University School of Medicine, Boston, Masssachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096366" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Brain/metabolism ; CRISPR-Cas Systems/genetics ; Enhancer Elements, Genetic/*genetics ; Epigenesis, Genetic/genetics ; *Gene Expression Regulation ; Genetic Engineering ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Homeodomain Proteins/metabolism ; Humans ; Models, Genetic ; Parkinson Disease/*genetics ; Pluripotent Stem Cells/metabolism ; Risk ; Transcription Factors/metabolism ; alpha-Synuclein/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2016-03-05
    Description: Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hnisz, Denes -- Weintraub, Abraham S -- Day, Daniel S -- Valton, Anne-Laure -- Bak, Rasmus O -- Li, Charles H -- Goldmann, Johanna -- Lajoie, Bryan R -- Fan, Zi Peng -- Sigova, Alla A -- Reddy, Jessica -- Borges-Rivera, Diego -- Lee, Tong Ihn -- Jaenisch, Rudolf -- Porteus, Matthew H -- Dekker, Job -- Young, Richard A -- AI120766/AI/NIAID NIH HHS/ -- CA109901/CA/NCI NIH HHS/ -- HG002668/HG/NHGRI NIH HHS/ -- MH104610/MH/NIMH NIH HHS/ -- NS088538/NS/NINDS NIH HHS/ -- R01 GM 112720/GM/NIGMS NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- R01 MH104610/MH/NIMH NIH HHS/ -- U01 DA 040588/DA/NIDA NIH HHS/ -- U01 HG007910/HG/NHGRI NIH HHS/ -- U01 R01 AI 117839/AI/NIAID NIH HHS/ -- U54 CA193419/CA/NCI NIH HHS/ -- U54 DK107980/DK/NIDDK NIH HHS/ -- U54 HG007010/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1454-8. doi: 10.1126/science.aad9024. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. ; Department of Pediatrics, Stanford University, Stanford, CA, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Howard Hughes Medical Institute. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. young@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940867" target="_blank"〉PubMed〈/a〉
    Keywords: *Chromosome Aberrations ; Chromosome Mapping ; *Gene Expression Regulation, Leukemic ; HEK293 Cells ; Humans ; Mutation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Proto-Oncogenes/*genetics ; *Sequence Deletion ; Transcriptional Activation ; *Translocation, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    ISSN: 0044-2313
    Keywords: Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Orthophosphoric acid hemihydrate, 2H3PO4 · H2O, forms monoclinic crystals with space group P21/c and four formula units in the unit cell (a = 7,387, b = 12.915, c = 7,850 Å; β = 109.8°). the crystal structure has been determined using three-dimensional photographic X-ray intensity data. The final R-factor for 832 observed independent reflections is 8.4%. The hydrogen atoms could not be located independently. Nevertheless it is possible to decide between an oxonium salt, H3O+H2PO4- · H3PO4, and a true acid hydrate, 2H3PO4 · H2O, from the observed pattern of P—O bond lenghts and O—P—O bond angles, which favours the second possibility.
    Notes: Orthophosphorsäure-hemihydrat, 2H3PO4 · H2O, kristallisiert monoklin in der Raumgruppe P 21/c mit vier Formeleinheiten in der Elementarzelle (a = 7,387, b = 12,915, c = 7,850 Å; β = 109,8°). Die Kristallstruktur wurde mit dreidimensionalen photographischen Röntgen-Intensitätendaten bestimmt. Der abschließende R-Faktor für 832 beobachtete unabhängige Reflexe beträgt 8,4%. Die Wasserstoffatome konnten nicht voraussetzungsfrei lokalisiert werden. Die Entscheidung zwischen einem Oxoniumsalz, H3PO+H2PO4- · H3PO4, und einem echten Säurehydrat, 2H3PO4 · H2, kann dennoch getroffen werden, und zwar auf Grund der beobachteten Abstufung der P—O-Bindungslängen und O—P—O-Bindungswinkel, die für die zweite Möglichkeit spricht.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    ISSN: 0044-8249
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    ISSN: 0044-8249
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    ISSN: 0570-0833
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    ISSN: 0570-0833
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    ISSN: 1432-2307
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zusammenfassung 1. Bei der Anwendung verschiedener Färbungsmethoden mit Sudan (übliche Lösung von Sudan III, gekochte Sudanlösung und Sudan-α-Naphthol) beziehen sich die Unterschiede bei der Darstellung der Lipoide nicht lediglich auf „integrale Lipoide” (lipoide Granula der Leukocyten, im Chondriom u. a.), sondern auch auf Lipoide von infiltrativem Charakter (Ablagerung von Lipoiden in den Gefäßen, sudanophiles Plasma, Ablagerungen der Lipoide in hyalinisierten Geweben usw.). 2. Die Unterschiede der Ergebnisse bei verschiedenen Färbungsmethoden mit Sudan hängen zum Teil davon ab, daß die Lipoide nicht frei, sondern an Eiweiß gebunden vorkommen. 3. Auf Grund der verschiedenen Färbungsmethoden mit Sudan kann man dem Verständnis der Eiweißstrukturen, mit welchen die lipoiden Substanzen verbunden sind, nähertreten. Bei Anwendung verschiedener Sudanlösungen ist man imstande, aus dem Grad und der Art der Lipoidfärbung auf die Veränderungen des Eiweißlipoidkomplexes bei pathologischen Zuständen zu schließen. 4. Bei der histologischen Untersuchung kann als Zeichen einer vollständigen Lipoidfärbung die positive Färbung der lipoiden Körnelung in den Leukocyten der myeloischen Reihe dienen.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 287 (1933), S. 587-601 
    ISSN: 1432-2307
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Cell & tissue research 27 (1937), S. 336-340 
    ISSN: 1432-0878
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...