Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice

Elife. 2020 Sep 29;9:e55911. doi: 10.7554/eLife.55911.

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.

Keywords: chromatin; genetics; genomics; histone deacatylase; huntington's disease; medium spiny neuron; mouse; neuroscience; repeat instability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus
  • Corpus Striatum / physiopathology*
  • Disease Models, Animal
  • Histone Deacetylase 2 / genetics*
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / enzymology
  • Huntington Disease / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / physiology*

Substances

  • Htt protein, mouse
  • Huntingtin Protein
  • Hdac2 protein, mouse
  • Histone Deacetylase 2
  • Histone Deacetylases
  • histone deacetylase 3

Associated data

  • GEO/GSE148440