Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models.
Transcriptional dysregulation plays a major role in the pathology of Huntington's disease (HD). However, the mechanisms causing selective downregulation of genes remain unknown. Histones regulate chromatin structure and thereby control gene expression; recent studies have demonstrated a therapeutic role for histone deacetylase (HDAC) inhibitors in polyglutamine diseases. This study demonstrates that despite no change in overall acetylated histone levels, histone H3 is hypo-acetylated at promoters of downregulated genes in R6/2 mice, ST14a and STHdh cells, as demonstrated by in vivo chromatin immunoprecipitation. In addition, HDAC inhibitor treatment increases association of acetylated histones with downregulated genes and corrects mRNA abnormalities. In contrast, there is a decrease in mRNA levels in wild-type cells following treatment with a histone acetyltransferase inhibitor. Although changes in histone acetylation correlate with decreased gene expression, histone hypo-acetylation may be a late event, as no hypo-acetylation is observed in 4-week-old R6/2 mice. Nevertheless, treatment with HDAC inhibitors corrects mRNA abnormalities through modification of histone proteins and may prove to be of therapeutic value in HD.
Sadri-Vakili
Ghazaleh
G
Department of Neurology, MassGeneral Institute for NeurodegenerativeDisease, Massachusetts General Hospital, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA.
Bouzou
Bérengère
B
Benn
Caroline L
CL
Kim
Mee-Ohk
MO
Chawla
Prianka
P
Overland
Ryan P
RP
Glajch
Kelly E
KE
Xia
Eva
E
Qiu
Zhihua
Z
Hersch
Steven M
SM
Clark
Timothy W
TW
Yohrling
George J
GJ
Cha
Jang-Ho J
JH
D000107:Acetylation; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D006657:Histones