Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by the expansion
of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes
of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused
by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be
alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase
(HDAC) enzymes. To determine which histone’s post-translational modifications (PTMs)
might play crucial roles in HD pathology, we investigated the phenotype-modifying
effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of
HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and
K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case
of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability,
longevity, neurodegeneration, motor activity, and circadian rhythm defects), while
H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects
of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered
the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude
that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor
to HD pathology.
