Memory-induced 3D chromatin architecture in Huntington's disease (HD) mice [4C-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157076 | GEO | 2022/10/06
REPOSITORIES: GEO
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Project description:Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.
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Project description:Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD),a neurodegenerative disease primarily affecting the striatum, remain unclear. Using slow progressing HDknockinmice,we have generated chromatin immunoprecipitation coupled with sequencing data for RNA polymerase II and histone modifications associated with active enhancers (H3K27ac) and repressive chromatin (H3K27me3), from neuronal, non-neuronal and bulk striatal tissue at two early disease stages. Data integration with cell type-specific transcriptomic databases shows that the HD mutation early accelerates age-related reprogramming of neuronal and glial cell identities at both epigenetic and transcriptional levels. Circular chromosome conformation capture followed by sequencing data using HD mouse striatum showed alterations both at neuronal super-enhancer and CAG expanded disease loci. Using these data to model higher-order chromatin architecture indicated that HD CAG expansion mutation impairs chromatin insulation and gene regulation. Thus, both age-dependent and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in HD striatum.
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Project description:Huntington’s disease (HD) is an incurable neurodegenerative disorder that is caused by CAG trinucleotide expansions in the huntingtin gene. However, the exact molecular and cellular mechanisms underlying the pathogenesis of HD are still not well understood. Immune signaling has been hypothesized to contribute to HD pathogenesis. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to access the transcriptional profiles of striatal cell types in control and R6/2 HD model mice that either had normal levels of, or were deficient for, the cytokine interleukin-6 (IL-6). Our results provide insights into the gene expression programs that are under the control of this important immune regulator in both a normal and HD model context.
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Project description:Huntington’s disease (HD) is a devastating disorder caused by an aberrant expansion of CAG repeats in the HTT gene. Striatal dysfunction has been widely studied in HD mouse models as part of the basal ganglia, the main brain areas affected in patients that explain the most evident symptomatology. However, cumulative evidence indicates that the retina can also be functionally altered with consequences for visual function and circadian rhythms. Moreover, the retina is the most exposed part of the CNS that can be used for monitoring the health status of patients using non-invasive techniques and for treatment screenings in preclinical models. To establish the retina as an appropriate tissue for HD studies, it is first required to link retinal alterations at the cellular and molecular levels with those of the inner brain. In this work, we confirmed that the retinas of R6/1 mice were functionally and morphologically affected, and suffered a rearrangement of its transcriptome as extensive as in the striatum. Tissue-enriched genes were downregulated in both areas, but a neuroinflammation signature was specific to the R6/1 retina through the glial activation that was apparently absent in the striatum of the same animals. These phenomena were confirmed in the zQ175 strain, and were accompanied by a differential impairment of the autophagy system between both tissues that may have implications for autophagic-based therapies in HD. Overall, these results demonstrated the suitability of the retina as a research model for HD and general neurodegeneration.
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Project description:Memory-induced 3D chromatin architecture in Huntington's disease (HD) mice [4C-seq]
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Project description: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. Analysis of striatum, cortex, and cerebellum from R6/2(300Q) transgenic mice before and after treatment with the HDAC inhibitor 4b
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