Modulation of nucleosome dynamics in Huntington's disease

Abstract

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.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Furthermore, chromonycin reduced the brain levels of 8-hydroxy-2-deoxyguanosine (8-OH2dG), a wellestablished marker of oxidative stress, in R6/2 mice. Importantly, similar results were obtained with a different HD transgenic mouse model (N171-82Q mice) (Stack et al, 2007b).…”

“…Since DNA/RNA-binding anthracyclines may have therapeutic potential by correcting pathological nucleosome changes and realigning transcription, Stack et al (2007b) have recently tested the effect of the anthracycline chromomycin in R6/2 mice. Chromomycin treatment (starting at postnatal day 28) realigned chromatin homeostasis, reduced histone H3 hypermethylation, and restored acetylation of histone H4 to wild-type levels.…”

Neuroprotective Effects of Synaptic Modulation in Huntington's Disease R6/2 Mice

“…Despite great progress, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. Recent interest has focused on significant alterations in transcriptional activity mediated by mutant huntingtin (mHtt) (Luthi-Carter et al, 2002;Ferrante et al, 2003;Sugars and Rubinsztein, 2003;Ryu et al, 2005Ryu et al, , 2006Stack et al, 2007). There is also substantial evidence that the polyglutamine expansion and subsequent protein aggregation may result in impaired mitochondrial function (Panov et al, 2002).…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…These findings support the role of epigenetic alterations in the R6/2 HD model and suggest that DNA-binding drugs, such as mithramycin, act by partially restoring perturbed histone modifications. Similarly, chromomycin restores the balance of methylation and acetylation of histone H3K9 towards greater acetylation in N171-82Q and R6/2 mice [70]. As a result, chromomycin landscapes transcriptionally active chromatin packaging and improves HD-related deficits and disease phenotype.…”

“…4). Altered expression of HMT and elevated H3K9me3 are linked to upstream transcriptional deregulation in both animal models of HD and in HD patients [65,66,70]. Thus, the increase of H3K9me3 level has been correlated with the formation of large constitutive heterochromatin domains and is thought to promote gene silencing in both global and local repression of transcription, including CHRM1 [68,71].…”