ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease.
Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients.
Ryu
Hoon
H
Geriatric Research Education and Clinical Center, Bedford Veteran's Affairs Medical Center, Bedford, MA 01730, USA. hoonryu@bu.edu
Lee
Junghee
J
Hagerty
Sean W
SW
Soh
Byoung Yul
BY
McAlpin
Sara E
SE
Cormier
Kerry A
KA
Smith
Karen M
KM
Ferrante
Robert J
RJ
D000368:Aged; D000818:Animals; D003538:Cystamine / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D008926:Plicamycin / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000235:genetics; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism; D015996:Survival Rate; D015854:Up-Regulation
D006657:Histones; D051705:Sp3 Transcription Factor; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; C516239:SETDB1 protein, mouse; D008926:Plicamycin; D003538:Cystamine