Targeting H3K4 trimethylation in Huntington disease

Abstract

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...

Epigenetic Modifications as Novel Therapeutic Targets For Huntington’S Disease

“…The H3K4me3 deficit is likely due to the upregulation of the specific histone demethylase Lysspecific demethylase 5C (KDM5C), also known as SMCX or Jarid1c, given the fact that reducing the level of the H3K4 demethylase SMCX/Jarid1c in primary neurons can rescue the downregulation of key neuronal genes caused by mHtt expression. Accordingly, knocking down SMCX/Jarid1c in primary neurons from HD model mice or Drosophila has proven to be neuronal protective [41].…”

Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

“…The number of glutamines in the polyQ stretch positively correlates with symptom severity and inversely correlates with the age of symptom onset (2). mHtt aggregates sequester many transcriptional factors via aberrant protein interactions, and these sequestrations cause transcriptional inhibition of genes such as brain-derived neurotrophic factor (BDNF) and its cognate receptors, which are responsible for neuronal survival and function (3)(4)(5)(6). Moreover, mHtt aggregates impair axonal transport and mitochondrial function, resulting in striatal neuron cell death in the basal ganglia and cortex (7,8).…”

Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

“…In an effort to determine chromatin structural modifications in the genes downregulated in HD, a genome-wide approach identified a specific H3K4me3 pattern, a mark of active chromatin and transcription initiation, which correlated with transcriptional dysregulation in the R6/2 HD mouse and human HD brain (Vashishtha et al 2013). Along similar lines, DNA methylation in promoter regions, which results in gene repression or silencing, was changed in a significant fraction of the genes altered in HD , although how mutant huntingtin triggers DNA methylation is currently unknown.…”