Human Molecular Genetics Advance Access originally published online on April 2, 2007
Human Molecular Genetics 2007 16(10):1164-1175; doi:10.1093/hmg/ddm064
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Modulation of nucleosome dynamics in Huntington's disease
1 Geriatric Research Education and Clinical Center, Bedford VA Medical Center, 200 Springs Road, Bedford, MA 01730, USA, 2 Department of Neurology, 3 Department of Pathology and Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA, 4 Mass General Institute of Neurodegenerative Disease, Building 114, 16th Street, Charlestown, MA 02129, USA and 5 Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland
* To whom correspondence should be addressed at: Tel: +1 7816872908; Fax: +1 7816873515; Email: rjferr{at}bu.edu
Received January 26, 2007; Revised March 7, 2007; Accepted March 13, 2007
Transcriptional dysregulation and aberrant chromatin remodeling are central features in the pathology of Huntington's disease (HD). In order to more fully characterize these pathogenic events, an assessment of histone profiles and associated gene changes were performed in transgenic N171–82Q (82Q) and R6/2 HD mice. Analyses revealed significant chromatin modification, resulting in reduced histone acetylation with concomitant increased histone methylation, consistent with findings observed in HD patients. While there are no known interventions that ameliorate or arrest HD progression, DNA/RNA-binding anthracyclines may provide significant therapeutic potential by correcting pathological nucleosome changes and realigning transcription. Two such anthracyclines, chromomycin and mithramycin, improved altered nucleosome homeostasis in HD mice, normalizing the chromatin pattern. There was a significant shift in the balance between methylation and acetylation in treated HD mice to that found in wild-type mice, resulting in greater acetylation of histone H3 at lysine 9 and promoting gene transcription. Gene expression profiling in anthracycline-treated HD mice showed molecular changes that correlate with disease correction, such that a subset of downregulated genes were upregulated with anthracycline treatment. Improved nucleosomal dynamics were concurrent with a significant improvement in the behavioral and neuropathological phenotype observed in HD mice. These data show the ability of anthracycline compounds to rebalance epigenetic histone modification and, as such, may provide the rationale for the design of human clinical trials in HD patients.
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