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Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis

Anikó Faragó1,2, Nóra Zsindely1, Anita Farkas1,2

  • 1Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary.

International Journal of Molecular Sciences
|December 11, 2022
PubMed

Insights

Huntington's Disease (HD) involves gene silencing. Modifying histone H3.3K14 acetylation in a fly model improved HD symptoms, suggesting epigenetic regulation is key for neurodegeneration.

Area of Science:

  • Epigenetics
  • Neurobiology
  • Genetics

Background:

  • Huntington's Disease (HD) is a fatal neurodegenerative disorder linked to CAG repeat expansion in the Huntingtin gene.
  • Transcriptional dysregulation, partly due to histone acetyltransferase (HAT) inhibition, contributes to HD neurodegeneration.
  • Modulating HAT or histone deacetylase (HDAC) activity can alleviate HD pathology.

Purpose of the Study:

  • To investigate the role of histone post-translational modifications (PTMs) in HD pathology.
  • To determine the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD.

Main Methods:

  • Created transgenic H3.3 with PTM mimetic mutations (K→Q: acetylated; K→R: non-modified; K→M: methylated) at lysine residues K9, K14, and K27.
  • Assessed the effects of these mutations on HD phenotypes in Drosophila, including viability, longevity, neurodegeneration, motor activity, and circadian rhythms.
  • Examined the interaction of H3.3K14 mutations with Gcn5 (HAT) and Sirt1 (HDAC) in the context of HD.

Main Results:

  • H3.3K14Q mutation significantly ameliorated all tested HD phenotypes in Drosophila.
  • H3.3K14R mutation exacerbated HD phenotypes.
  • H3.3K14Q expression counteracted the detrimental effects of reduced Gcn5 activity and partially mitigated the beneficial effects of Sirt1.

Conclusions:

  • The acetylation of H3.3K14, particularly dependent on Gcn5, plays a crucial role in modulating Huntington's Disease pathology.
  • Targeting H3.3K14 acetylation represents a potential therapeutic strategy for HD.

Keywords:
DrosophilaHuntington’s diseaseanimal modelepigeneticshistonehistone acetylationneurodegeneration

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