Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage

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Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2 300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2 300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.rologic disorder caused by a CAG repeat expansion within the coding region of the HD gene (Htt), resulting in a mutant protein (htt) with a lengthened polyglutamine tract (1). Mutant htt protein has been shown to disrupt transcription by multiple mechanisms, but it is unclear which are most important to pathology (2-4). By interacting with specific transcription factors, htt can alter the expression of clusters of genes controlled by those factors. For example, several genes driven by Sp1, which has been shown to interact with htt (5, 6), show decreased mRNA expression in human HD and in mouse models of HD (7). Alternatively, htt may have more global effects on transcription by disrupting core transcriptional machinery (8, 9) or by altering posttranslational modifications of histones, resulting in condensed chromatin structure (10-13). Understanding the basis for transcriptional dysregulation is important for choosing appropriate drug-discovery strategies.Manifestations of transcriptional dysregulation are evident from several gene-profiling studies, which have revealed alterations in the expression of large numbers of genes in the brains of different HD mouse models and in human subjects with HD (7, 14-16). Many of the expression changes in mouse models are observed in early stages of illness before the onset of symptoms, suggesting that gene expression alterations may be pathogenic.Because o...

Section: Hdaci 4b Treatment Ameliorates Gene Expression Abnormalities Insupporting

confidence: 92%

The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

Thomas

Coppola²,

Desplats³

et al. 2008

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258

“…Although the YAC128 mouse is one of the most comprehensive and well-established models of HD, no mouse model recapitulates all molecular manifestations of human HD. In fact, it is reported that YAC128 mice fail to show concordant gene expression changes with human HD until the mice are 24 mo of age (27), whereas our studies of altered HACE1 expression in YAC128 mice were restricted to mice 12 mo of age or younger. Additionally, in a recent study of 12 genes that were differentially expressed in the striatum of YAC128 versus control mouse striatum, only four of these 12 genes were concordantly changed when assessed in human HD versus control striatum (28).…”

Section: Hace1 Mediatesmentioning

confidence: 73%

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rotblat

Southwell

Ehrnhoefer

et al. 2014

Self Cite

Oxidative stress plays a key role in late onset diseases including cancer and neurodegenerative diseases such as Huntington disease. Therefore, uncovering regulators of the antioxidant stress responses is important for understanding the course of these diseases. Indeed, the nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidative stress response, is deregulated in both cancer and neurodegeneration. Similar to NRF2, the tumor suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays a protective role against stress-induced tumorigenesis in mice, but its roles in the antioxidative stress response or its involvement in neurodegeneration have not been investigated. To this end we examined Hace1 WT and KO mice and found that Hace1 KO animals exhibited increased oxidative stress in brain and that the antioxidative stress response was impaired. Moreover, HACE1 was found to be essential for optimal NRF2 activation in cells challenged with oxidative stress, as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein synthesis, leading to lower tolerance against oxidative stress triggers. Strikingly, we found a reduction of HACE1 levels in the striatum of Huntington disease patients, implicating HACE1 in the pathology of Huntington disease. Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells provided protection against mutant Huntingtin-induced redox imbalance and hypersensitivity to oxidative stress, by augmenting NRF2 functions. These findings reveal that the tumor suppressor HACE1 plays a role in the NRF2 antioxidative stress response pathway and in neurodegeneration.

“…To evaluate this hypothesis, we focused on H3K4 trimethylation (H3K4me3), a mark of transcription start sites (TSSs) and active chromatin (6-8). Growing evidence suggests that this mark is plastic and modulated in conditions of chronic stress, developmental disorders, psychiatric disorders (9-11) as well as during long-term memory consolidation from contextual fear conditioning (12), suggesting a critical function in brain.We first investigated H3K4me3 in the R6/2 mouse model of HD, which shows patterns of transcriptional dysregulation similar to postmortem HD brain (13,14). Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5, 15).…”

mentioning

confidence: 99%

“…We first investigated H3K4me3 in the R6/2 mouse model of HD, which shows patterns of transcriptional dysregulation similar to postmortem HD brain (13,14). Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5, 15).…”

mentioning

confidence: 99%

Targeting H3K4 trimethylation in Huntington disease

Vashishtha

Ng²,

Yildirim³

et al. 2013

Self Cite

151

173

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.polyglutamine | neurodegeneration H untington disease (HD), a neurodegenerative disease (1, 2) characterized by cognitive dysfunction, psychiatric symptoms, and choreic movements (2), exhibits brain region-specific neuronal degeneration in the striatum and cortex. Currently, no disease-modifying treatment is available. The genetic basis of HD is the expansion of an in-frame CAG repeat sequence encoding polyglutamine. Progressive transcriptional dysregulation in both cortex and striatum and atrophy of the cortex are characteristic features (3). Transcriptional repression of key neuronal transcripts, including neurotransmitters, growth factors, and their cognate receptors, is consistently observed and implicated in disease pathogenesis. Among the critical genes whose expression is repressed in HD mouse models and human brain tissue are the dopamine receptor 2 (Drd2), preproenkephalin (Penk1), the cannabinoid receptor (Cb2), and brain-derived neurotrophic factor (Bdnf) (4, 5).We hypothesized that a central event in the pathological program underlying transcriptional dysregulation includes alterations in chromatin structure in the regulatory regions of genes down-regulated in HD. To evaluate this hypothesis, we focused on H3K4 trimethylation (H3K4me3), a mark of transcription start sites (TSSs) and active chromatin (6-8). Growing evidence suggests that this mark is plastic and modulated in conditions of chronic stress, developmental disorders, psychiatric disorders (9-11) as well as during long-term memory consolidation from contextual fear conditioning (12), suggesting a critical function in brain.We first investigated H3K4me3 in the R6/2 mouse model of HD, which shows patterns of transcriptional dysregulation similar to postmortem HD brain (13,14). Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5, 15). The potential significance of Bdnf in HD is reflected by transcriptional profiling (16) and therapeutic preclinical studies (17,18). Because H3K4me3 levels were lowered at Bdnf and other promoters in R6/2 mice and key neuronal genes in human HD brain cortex and striata, we expanded our approach to investigate the genome-wide relationship between H3K4me3 an...