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Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington’s disease

ABSTRACT: Abstract - Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington’s disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.

ORGANISM(S): Mus musculus

PROVIDER: GSE42107 | GEO | 2013/01/03

SECONDARY ACCESSION(S): PRJNA179146

REPOSITORIES: GEO

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Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of HuntingtonM-bM-^@M-^Ys disease

Project description:Abstract - Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in HuntingtonM-bM-^@M-^Ys disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival. Biological replicates total RNA samples from 2 cell types (Hdh7/7 and Hdh109/109) cells were used. Expression in 'HD' cells (Hdh109/109) was compared with expression in wildtype (Hdh7/7) cells.

2013-01-03 | E-GEOD-42107 | biostudies-arrayexpress

ChIP-seq of HTT protein in mouse cortex following HTT knockdown

Project description:Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but direct relationships between the huntingtin (HTT) protein and chromatin remain poorly described. Here, using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that HTT reproducibly occupies specific locations in the mouse genome, including thousands of genomic loci that are differentially occupied in striatal tissue from a knock-in mouse model of the HD mutation (B6.HttQ111/+) versus wildtype controls. ChIP-seq of histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with trimethylation of histone 3 lysine 27 (H3K27me3), a repressive chromatin mark. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/+ vs. wildtype mice predicted increased H3K27me3, reduced histone 3 lysine 4 (H3K4me3), a marker of poised and active promoters, and down-regulated gene expression. Altered huntingtin-chromatin interactions may therefore play a direct role in driving transcriptional dysregulation in HD.

2023-05-16 | GSE150748 | GEO

ChIP-seq of histone modifications and EZH2 in the striatum of four-month-old HttQ111/+ and wildtype mice

2023-05-16 | GSE150747 | GEO

Spatiotemporal proteomic profiling of Huntington's disease mice reveals widespread loss of protein function

Project description:Huntington's disease (HD) is characterized by the aggregation of polyglutamine-expanded huntingtin (HTT), proceeding from soluble oligomers to end-stage inclusions. The molecular mechanisms of how protein aggregation leads to neuronal dysfunction are not well understood. We employed mass spectrometry-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. We show that extensive remodeling of the soluble brain proteome correlates with changes in insoluble aggregate formation during disease progression. In-depth characterization of HTT inclusion bodies uncovered an unprecedented complexity of several hundred proteins. Sequestration to inclusions was dependent on protein expression levels and the presence of aggregation-prone amino acid sequence features, such as low-complexity regions or coiled-coil domains. Overexpression of several sequestered proteins ameliorated HTT toxicity and modified the aggregation behavior in an in vitro model of HD. Our study provides a comprehensive and spatiotemporally-resolved proteome resource of HD progression, indicating that widespread loss of protein function contributes to aggregate-mediated toxicity.

2017-11-24 | PXD004973 | Pride

Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice [INCPMPM-17698]

Project description:Huntington’s disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutant Htt by targeting Spt4/Spt5 or the Spt5-PolII transcription elongation complexes was proposed as a potential therapy. We report the identification of SPI-24 and SPI-77 small molecule inhibitors of Spt5-PolII that selectively lower mutant Htt. In the BACHD mouse model of HD, direct delivery to the striatum, subcutaneous injection and oral administration of these inhibitors diminished mutant Htt levels, ameliorated mitochondrial dysfunction and restored BDNF expression. Prolonged treatment attenuated motor and anxious-like phenotypes of HD mice and delayed disease deterioration. SPI-24 long-term treatment had no side-effects or global changes in gene expression. Mechanistically, SPIs reduce Spt5 and PolII occupancies of mutant Htt. Thus, SPIs can be an effective therapeutic strategy for HD.

2023-11-20 | GSE225789 | GEO

Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice [INCPMPM-16068]

2023-11-20 | GSE225788 | GEO

Expression data from a cell model of Huntington disease

Project description:Huntington disease (HD) is associated with increased nuclear accumulation of the repressor element-1 silencing transcription factor (REST) which govens a huge gene network. An alternative REST splicing event (∆E3) eliminates a motif essential for nuclear targeting of REST. We used Affymetrix’s GeneChip® Mouse Gene 2.0 ST Array to compare global transcription between STHdhQ111/Q111 cells (a cell model of HD) treated with specific antisense oligos (ASOs) inducing ∆E3 and a control oligo, with a comparison to normal STHdhQ7/Q7 cells.

2016-01-25 | GSE77194 | GEO

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease

Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder that is caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD in the lab has proven challenging as rodent models poorly reproduce the disease process and cellular models fail to include age-dependent processes crucial to the expression of the disease clinically. Here we generated induced neurons (iNs) through direct reprogramming of skin fibroblasts from HD-patients. This resulted in the generation of patient-derived HD neurons that retained age-dependent epigentic characteristics of the donors. Using these cells, we then undertook a proteomic analysis and demonstrated there was an alteration in the CAMKK-AMPK pathway and autophagy in these HD-iNs, compared to healthy control iN cells. In line with this, HD-iNs displayed a distinct subcellular alteration in autophagy, specifically in the neurites, characterized by a reduction in the transport of late autophagic structures between neurites and the soma and subsequent cargo degradation. In addition to which the HD-iNs displayed shorter, smaller and fewer neurites. CRISPRi-mediated silencing of HTT (both wt and mutant) did not rescue the morphology nor could this rescue the autophagic defect in HD-iNs and indeed resulted in additional autophagy alterations when done using ctrl-iNs, highlighting the importance of wild type HTT in neuronal autophagy. In summary, our results have identified a distinct subcellular autophagy impairment in aged patient derived HD-neurons. In addition, we have shown a role for normal wt Htt in autophagy. Together this work provides a new rational for future development of autophagy activation therapies while also highlighting problems that may arise using non allele specific htt silencing approaches, some of which are now in clinical trials.

2022-10-14 | PXD024286 | Pride

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease

Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD in the lab has proven challenging as rodent models poorly reproduce the disease process and cellular models fail to include age-dependent processes crucial to the disease. Here we generated induced neurons (iNs) that retained age-dependent epigenetic characteristics of the donors through direct reprogramming of skin fibroblasts. HD-iNs displayed a transcriptionally regulated, distinct neurite specific alteration in autophagy, characterized by reduced transport of late autophagic structures and subsequent cargo degradation. In addition, HD-iNs displayed shorter, smaller and fewer neurites. CRISPRi-mediated silencing of both HTT alleles did not rescue the morphology nor the autophagic defect in HD-iNs. Strikingly, it resulted in additional autophagy alterations when done using ctrl-iNs, highlighting the importance of wt HTT in neuronal autophagy. In summary, our results have identified a distinct subcellular autophagy impairment in aged patient derived HD-neurons. In addition, we have shown a role for normal wt HTT in autophagy. Together this work provides a new rational for future development of autophagy activation therapies while also highlighting problems that may arise using non allele specific HTT silencing approaches, some of which are now in clinical trials.

2022-02-01 | GSE167104 | GEO

Polycomb Repressor Complex2 and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype

Project description:These experiments were designed to test the hypothesis that REST and Polycomb Repressor Complex 2 function cooperatively in undifferentiated ESCs. Our results show that H3K27me3-enriched genes show no de-repression in REST-/- ESCs, while REST target genes show significant de-repression.

2014-09-30 | GSE59442 | GEO

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