Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice
Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level...
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Language: | English |
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eLife Sciences Publications Ltd
2020-09-01
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Online Access: | https://elifesciences.org/articles/55911 |
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author | Marina Kovalenko Serkan Erdin Marissa A Andrew Jason St Claire Melissa Shaughnessey Leroy Hubert João Luís Neto Alexei Stortchevoi Daniel M Fass Ricardo Mouro Pinto Stephen J Haggarty John H Wilson Michael E Talkowski Vanessa C Wheeler |
author_facet | Marina Kovalenko Serkan Erdin Marissa A Andrew Jason St Claire Melissa Shaughnessey Leroy Hubert João Luís Neto Alexei Stortchevoi Daniel M Fass Ricardo Mouro Pinto Stephen J Haggarty John H Wilson Michael E Talkowski Vanessa C Wheeler |
author_sort | Marina Kovalenko |
collection | DOAJ |
description | Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in HttQ111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the HttQ111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in medium-spiny neurons and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD. |
first_indexed | 2024-04-11T09:04:58Z |
format | Article |
id | doaj.art-7ec6f42abf9f427c8434769cf8737ee8 |
institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-11T09:04:58Z |
publishDate | 2020-09-01 |
publisher | eLife Sciences Publications Ltd |
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series | eLife |
spelling | doaj.art-7ec6f42abf9f427c8434769cf8737ee82022-12-22T04:32:39ZengeLife Sciences Publications LtdeLife2050-084X2020-09-01910.7554/eLife.55911Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease miceMarina Kovalenko0Serkan Erdin1https://orcid.org/0000-0001-6587-2625Marissa A Andrew2Jason St Claire3Melissa Shaughnessey4Leroy Hubert5João Luís Neto6https://orcid.org/0000-0003-0863-158XAlexei Stortchevoi7Daniel M Fass8https://orcid.org/0000-0003-0018-8093Ricardo Mouro Pinto9Stephen J Haggarty10https://orcid.org/0000-0002-7872-168XJohn H Wilson11Michael E Talkowski12Vanessa C Wheeler13https://orcid.org/0000-0003-2619-589XCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United States; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United States; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United States; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United StatesVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United States; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine, Harvard Medical School, Boston, United States; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United StatesSomatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in HttQ111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the HttQ111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in medium-spiny neurons and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.https://elifesciences.org/articles/55911huntington's diseaserepeat instabilityhistone deacatylasechromatinmedium spiny neuron |
spellingShingle | Marina Kovalenko Serkan Erdin Marissa A Andrew Jason St Claire Melissa Shaughnessey Leroy Hubert João Luís Neto Alexei Stortchevoi Daniel M Fass Ricardo Mouro Pinto Stephen J Haggarty John H Wilson Michael E Talkowski Vanessa C Wheeler Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice eLife huntington's disease repeat instability histone deacatylase chromatin medium spiny neuron |
title | Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice |
title_full | Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice |
title_fullStr | Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice |
title_full_unstemmed | Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice |
title_short | Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice |
title_sort | histone deacetylase knockouts modify transcription cag instability and nuclear pathology in huntington disease mice |
topic | huntington's disease repeat instability histone deacatylase chromatin medium spiny neuron |
url | https://elifesciences.org/articles/55911 |
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