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  • 1
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    MED23 mutation links intellectual disability to dysregulation of immediate early gene expression (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-08-27
    Description: MED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hashimoto, Satoru -- Boissel, Sarah -- Zarhrate, Mohammed -- Rio, Marlene -- Munnich, Arnold -- Egly, Jean-Marc -- Colleaux, Laurence -- New York, N.Y. -- Science. 2011 Aug 26;333(6046):1161-3. doi: 10.1126/science.1206638.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/Universite de Strasbourg, BP 163, 67404 Illkirch Cedex, C. U. Strasbourg, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21868677" target="_blank"〉PubMed〈/a〉
    Keywords: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Cells, Cultured ; Chromatin Immunoprecipitation ; Early Growth Response Protein 1/genetics ; Female ; *Gene Expression Regulation ; *Genes, Immediate-Early ; Genes, fos ; Genes, jun ; Histones/metabolism ; Humans ; Intellectual Disability/*genetics ; Male ; Mediator Complex/*genetics ; *Mutation, Missense ; Pedigree ; Promoter Regions, Genetic ; Transcription Factors/metabolism ; Transcriptional Activation ; ets-Domain Protein Elk-1/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering (2014)
    Oxford University Press
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    Publication Date: 2014-02-28
    Description: Rare-cleaving endonucleases have emerged as important tools for making targeted genome modifications. While multiple platforms are now available to generate reagents for research applications, each existing platform has significant limitations in one or more of three key properties necessary for therapeutic application: efficiency of cleavage at the desired target site, specificity of cleavage (i.e. rate of cleavage at ‘off-target’ sites), and efficient/facile means for delivery to desired target cells. Here, we describe the development of a single-chain rare-cleaving nuclease architecture, which we designate ‘megaTAL’, in which the DNA binding region of a transcription activator-like (TAL) effector is used to ‘address’ a site-specific meganuclease adjacent to a single desired genomic target site. This architecture allows the generation of extremely active and hyper-specific compact nucleases that are compatible with all current viral and nonviral cell delivery methods.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Progressive engineering of a homing endonuclease genome editing reagent for the murine X-linked immunodeficiency locus (2014)
    Oxford University Press
    Details
    Publication Date: 2014-06-03
    Description: LAGLIDADG homing endonucleases (LHEs) are compact endonucleases with 20–22 bp recognition sites, and thus are ideal scaffolds for engineering site-specific DNA cleavage enzymes for genome editing applications. Here, we describe a general approach to LHE engineering that combines rational design with directed evolution, using a yeast surface display high-throughput cleavage selection. This approach was employed to alter the binding and cleavage specificity of the I-Anil LHE to recognize a mutation in the mouse Bruton tyrosine kinase (Btk) gene causative for mouse X-linked immunodeficiency (XID)—a model of human X-linked agammaglobulinemia (XLA). The required re-targeting of I-AniI involved progressive resculpting of the DNA contact interface to accommodate nine base differences from the native cleavage sequence. The enzyme emerging from the progressive engineering process was specific for the XID mutant allele versus the wild-type (WT) allele, and exhibited activity equivalent to WT I-AniI in vitro and in cellulo reporter assays. Fusion of the enzyme to a site-specific DNA binding domain of transcription activator-like effector (TALE) resulted in a further enhancement of gene editing efficiency. These results illustrate the potential of LHE enzymes as specific and efficient tools for therapeutic genome engineering.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Reprogramming homing endonuclease specificity through computational design and directed evolution (2014)
    Oxford University Press
    Details
    Publication Date: 2014-02-28
    Description: Homing endonucleases (HEs) can be used to induce targeted genome modification to reduce the fitness of pathogen vectors such as the malaria-transmitting Anopheles gambiae and to correct deleterious mutations in genetic diseases. We describe the creation of an extensive set of HE variants with novel DNA cleavage specificities using an integrated experimental and computational approach. Using computational modeling and an improved selection strategy, which optimizes specificity in addition to activity, we engineered an endonuclease to cleave in a gene associated with Anopheles sterility and another to cleave near a mutation that causes pyruvate kinase deficiency. In the course of this work we observed unanticipated context-dependence between bases which will need to be mechanistically understood for reprogramming of specificity to succeed more generally.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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