Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice
- Massachusetts General Hospital, United States
- Massachusetts General Hospital/Broad Institute, United States
- Baylor College of Medicine, United States
- Massachusetts General Hospital, Harvard Medical School, United States
Abstract
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 MSNs and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.
Data availability
RNA-Seq data is deposited in GEO, under the accession number GSE148440
Article and author information
Author details
Stephen J Haggarty
Funding
Huntington Society of Canada (New Pathways Research Grant)
- Vanessa C Wheeler
National Institutes of Health (NS049206)
- Vanessa C Wheeler
Huntington's Disease Society of America (Berman Topper Career Development Award)
- Ricardo Mouro Pinto
National Institutes of Health (GM38219)
- John H Wilson
National Institutes of Health (EY11731)
- John H Wilson
National Institutes of Health (1F3HG004918)
- Leroy Hubert
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Harry T Orr, University of Minnesota, United States
Ethics
Animal experimentation: This study was carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health under an approved protocol (2009N000216) of the Massachusetts General Hospital Subcommittee on Research Animal Care.
Version history
- Received: April 15, 2020
- Accepted: September 28, 2020
- Accepted Manuscript published: September 29, 2020 (version 1)
- Version of Record published: October 22, 2020 (version 2)
Copyright
© 2020, Kovalenko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice
eLife 9:e55911.
https://doi.org/10.7554/eLife.55911
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