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Updated: Dec 7, 2025
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice
Marina Kovalenko1, Serkan Erdin1,2, Marissa A Andrew1
1Center for Genomic Medicine, Harvard Medical School, Boston, 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 medium-spiny neurons and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.
Insights
Genetic knockout of HDAC2 and HDAC3 in Huntington's disease (HD) mouse models partially reduced CAG repeat expansion. HDAC2 knockout notably altered gene expression, suggesting it as a therapeutic target for HD transcriptional dysregulation.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is characterized by CAG repeat expansion in the huntingtin gene, leading to neuronal dysfunction and death.
- Transcriptional dysregulation is a key pathogenic mechanism in HD, but specific modifiers are not fully understood.
Purpose of the Study:
- To identify genetic modifiers of CAG repeat expansion and downstream pathogenesis in HD.
- To investigate the role of Histone Deacetylase 2 (HDAC2) and HDAC3 in HD.
Main Methods:
- Utilized HttQ111 mouse model of Huntington's disease.
- Performed genetic knockout of Hdac2 and Hdac3 in medium-spiny striatal neurons.
- Assessed CAG repeat expansion, nuclear huntingtin pathology, and transcriptional changes.
Main Results:
- Both Hdac2 and Hdac3 knockouts moderately reduced CAG repeat expansion.
- Hdac2 knockout decreased nuclear huntingtin pathology.
- Hdac2 knockout induced significant transcriptional changes, modifying HttQ111-induced dysregulation.
Conclusions:
- HDAC2 and HDAC3 are novel modifiers of HD pathogenesis in medium-spiny neurons.
- HDAC2 plays a complex role in HD, independent of CAG repeat instability.
- Targeting transcriptional dysregulation via HDAC2 inhibition may offer therapeutic potential for HD.
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