Bromodomain inhibitors regulate the C9ORF72 locus in ALS
Identifieur interne : 000808 ( Main/Exploration ); précédent : 000807; suivant : 000809Bromodomain inhibitors regulate the C9ORF72 locus in ALS
Auteurs : Zane Zeier [États-Unis] ; Rustam Esanov [États-Unis] ; Kinsley C. Belle ; Claude-Henry Volmar [États-Unis] ; Andrea L. Johnstone [États-Unis] ; Paul Halley [États-Unis] ; Brooke A. Derosa ; Nathalie Khoury [États-Unis] ; Marka Van Blitterswijk ; Rosa Rademakers ; Jeffrey Albert ; Shaun P. Brothers [États-Unis] ; Joanne Wuu ; Derek M. Dykxhoorn ; Michael Benatar ; Claes Wahlestedt [États-Unis]Source :
- Experimental neurology [ 0014-4886 ] ; 2015.
Abstract
A hexanucleotide repeat expansion residing within the
Url:
DOI: 10.1016/j.expneurol.2015.06.017
PubMed: 26099177
PubMed Central: 4586400
Affiliations:
Links toward previous steps (curation, corpus...)
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Le document en format XML
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locus in ALS</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Bromodomain inhibitors regulate the <italic>C9ORF72</italic>
locus in ALS</title>
<author><name sortKey="Zeier, Zane" sort="Zeier, Zane" uniqKey="Zeier Z" first="Zane" last="Zeier">Zane Zeier</name>
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<author><name sortKey="Esanov, Rustam" sort="Esanov, Rustam" uniqKey="Esanov R" first="Rustam" last="Esanov">Rustam Esanov</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Belle, Kinsley C" sort="Belle, Kinsley C" uniqKey="Belle K" first="Kinsley C." last="Belle">Kinsley C. Belle</name>
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<wicri:noCountry code="subfield">University of Miami Miller School of Medicine</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Volmar, Claude Henry" sort="Volmar, Claude Henry" uniqKey="Volmar C" first="Claude-Henry" last="Volmar">Claude-Henry Volmar</name>
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</author>
<author><name sortKey="Johnstone, Andrea L" sort="Johnstone, Andrea L" uniqKey="Johnstone A" first="Andrea L." last="Johnstone">Andrea L. Johnstone</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136</wicri:regionArea>
<wicri:noRegion>33136</wicri:noRegion>
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<author><name sortKey="Halley, Paul" sort="Halley, Paul" uniqKey="Halley P" first="Paul" last="Halley">Paul Halley</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136</wicri:regionArea>
<wicri:noRegion>33136</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Derosa, Brooke A" sort="Derosa, Brooke A" uniqKey="Derosa B" first="Brooke A." last="Derosa">Brooke A. Derosa</name>
<affiliation><nlm:aff id="A5">John P. Hussman Institute for Human Genomics and the Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Miami Miller School of Medicine</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Khoury, Nathalie" sort="Khoury, Nathalie" uniqKey="Khoury N" first="Nathalie" last="Khoury">Nathalie Khoury</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136</wicri:regionArea>
<wicri:noRegion>33136</wicri:noRegion>
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</author>
<author><name sortKey="Van Blitterswijk, Marka" sort="Van Blitterswijk, Marka" uniqKey="Van Blitterswijk M" first="Marka" last="Van Blitterswijk">Marka Van Blitterswijk</name>
<affiliation><nlm:aff id="A2">Mayo Clinic, Jacksonville FL</nlm:aff>
<wicri:noCountry code="subfield">Jacksonville FL</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name>
<affiliation><nlm:aff id="A2">Mayo Clinic, Jacksonville FL</nlm:aff>
<wicri:noCountry code="subfield">Jacksonville FL</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Albert, Jeffrey" sort="Albert, Jeffrey" uniqKey="Albert J" first="Jeffrey" last="Albert">Jeffrey Albert</name>
<affiliation><nlm:aff id="A3">IntelliSynRD, Montreal Canada</nlm:aff>
<wicri:noCountry code="subfield">Montreal Canada</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Brothers, Shaun P" sort="Brothers, Shaun P" uniqKey="Brothers S" first="Shaun P." last="Brothers">Shaun P. Brothers</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136</wicri:regionArea>
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<author><name sortKey="Wuu, Joanne" sort="Wuu, Joanne" uniqKey="Wuu J" first="Joanne" last="Wuu">Joanne Wuu</name>
<affiliation><nlm:aff id="A4">Department of Neurology, University of Miami Miller School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Miami Miller School of Medicine</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Dykxhoorn, Derek M" sort="Dykxhoorn, Derek M" uniqKey="Dykxhoorn D" first="Derek M." last="Dykxhoorn">Derek M. Dykxhoorn</name>
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<wicri:noCountry code="subfield">University of Miami Miller School of Medicine</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Benatar, Michael" sort="Benatar, Michael" uniqKey="Benatar M" first="Michael" last="Benatar">Michael Benatar</name>
<affiliation><nlm:aff id="A4">Department of Neurology, University of Miami Miller School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Miami Miller School of Medicine</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wahlestedt, Claes" sort="Wahlestedt, Claes" uniqKey="Wahlestedt C" first="Claes" last="Wahlestedt">Claes Wahlestedt</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<series><title level="j">Experimental neurology</title>
<idno type="ISSN">0014-4886</idno>
<idno type="eISSN">1090-2430</idno>
<imprint><date when="2015">2015</date>
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<front><div type="abstract" xml:lang="en"><p id="P2">A hexanucleotide repeat expansion residing within the <italic>C9ORF72</italic>
gene represents the most common known cause of amyotrophic lateral sclerosis (ALS) and places the disease among a growing family of repeat expansion disorders. The presence of RNA foci, repeat-associated translation products, and sequestration of RNA binding proteins suggests that toxic RNA gain-of-function contributes to pathology while <italic>C9ORF72</italic>
haploinsufficiency may be an additional pathological factor. One viable therapeutic strategy for treating expansion diseases is the use of small molecule inhibitors of epigenetic modifier proteins to reactivate expanded genetic loci. Indeed, previous studies have established proof of this principle by increasing the drug-induced expression of expanded (and abnormally heterochromatinized) FMR1, FXN and <italic>C9ORF72</italic>
genes in respective patient cells. While epigenetic modifier proteins are increasingly recognized as druggable targets, there have been few screening strategies to address this avenue of drug discovery in the context of expansion diseases. Here we utilize a semi-high-throughput gene expression based screen to identify siRNAs and small molecule inhibitors of epigenetic modifier proteins that regulate <italic>C9ORF72</italic>
RNA in patient fibroblasts, lymphocytes and reprogrammed motor neurons. We found that several bromodomain small molecule inhibitors increase the expression of <italic>C9ORF72</italic>
mRNA and pre-mRNA without affecting repressive epigenetic signatures of expanded <italic>C9ORF72</italic>
alleles. These data suggest that bromodomain inhibition increases the expression of unexpanded <italic>C9ORF72</italic>
alleles and may therefore compensate for haploinsufficiency without increasing the production of toxic RNA and protein products, thereby conferring therapeutic value.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
</list>
<tree><noCountry><name sortKey="Albert, Jeffrey" sort="Albert, Jeffrey" uniqKey="Albert J" first="Jeffrey" last="Albert">Jeffrey Albert</name>
<name sortKey="Belle, Kinsley C" sort="Belle, Kinsley C" uniqKey="Belle K" first="Kinsley C." last="Belle">Kinsley C. Belle</name>
<name sortKey="Benatar, Michael" sort="Benatar, Michael" uniqKey="Benatar M" first="Michael" last="Benatar">Michael Benatar</name>
<name sortKey="Derosa, Brooke A" sort="Derosa, Brooke A" uniqKey="Derosa B" first="Brooke A." last="Derosa">Brooke A. Derosa</name>
<name sortKey="Dykxhoorn, Derek M" sort="Dykxhoorn, Derek M" uniqKey="Dykxhoorn D" first="Derek M." last="Dykxhoorn">Derek M. Dykxhoorn</name>
<name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name>
<name sortKey="Van Blitterswijk, Marka" sort="Van Blitterswijk, Marka" uniqKey="Van Blitterswijk M" first="Marka" last="Van Blitterswijk">Marka Van Blitterswijk</name>
<name sortKey="Wuu, Joanne" sort="Wuu, Joanne" uniqKey="Wuu J" first="Joanne" last="Wuu">Joanne Wuu</name>
</noCountry>
<country name="États-Unis"><noRegion><name sortKey="Zeier, Zane" sort="Zeier, Zane" uniqKey="Zeier Z" first="Zane" last="Zeier">Zane Zeier</name>
</noRegion>
<name sortKey="Brothers, Shaun P" sort="Brothers, Shaun P" uniqKey="Brothers S" first="Shaun P." last="Brothers">Shaun P. Brothers</name>
<name sortKey="Esanov, Rustam" sort="Esanov, Rustam" uniqKey="Esanov R" first="Rustam" last="Esanov">Rustam Esanov</name>
<name sortKey="Halley, Paul" sort="Halley, Paul" uniqKey="Halley P" first="Paul" last="Halley">Paul Halley</name>
<name sortKey="Johnstone, Andrea L" sort="Johnstone, Andrea L" uniqKey="Johnstone A" first="Andrea L." last="Johnstone">Andrea L. Johnstone</name>
<name sortKey="Khoury, Nathalie" sort="Khoury, Nathalie" uniqKey="Khoury N" first="Nathalie" last="Khoury">Nathalie Khoury</name>
<name sortKey="Volmar, Claude Henry" sort="Volmar, Claude Henry" uniqKey="Volmar C" first="Claude-Henry" last="Volmar">Claude-Henry Volmar</name>
<name sortKey="Wahlestedt, Claes" sort="Wahlestedt, Claes" uniqKey="Wahlestedt C" first="Claes" last="Wahlestedt">Claes Wahlestedt</name>
</country>
</tree>
</affiliations>
</record>
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