Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE150747 | GEO | 2023/05/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Molecular and cellular consequences of genetic knockout of Hdac2 and Hdac3 in striatal medium spiny neurons of Huntington's disease knock-in mice

Project description:Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process resulting in neuronal cell death. Although mechanisms of neuronal toxicity are not well delineated, transcriptional dysregulation is a likely contributor. Chromatin modifiers are implicated in both mechanisms of CAG instability and transcriptional dysregulation. Here, we tested whether histone deacetylase genes Hdac2 and Hdac3 modify molecular and cellular phenotypes in HttQ111 knock-in mice using conditional knockouts in striatal medium-spiny striatal neurons (MSNs) exhibiting extensive CAG expansion and exquisite disease vulnerability. MSN-specific Hdac2 or Hdac3 knockout attenuated CAG expansion, with the Hdac2 knockout impacting nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included reversal of transcriptional dysregulation elicited by the HttQ111 allele. Our results identify novel modifiers of CAG expansion in MSNs, providing testable mechanistic hypotheses, and a potentially complex relationship between Htt and Hdac2 with implications for targeting transcriptional dysregulation in HD.

2020-06-01 | GSE148440 | GEO

Genome-scale chromatin interaction data for huntingtin from mouse striatal tissue

Project description:Transcriptional changes are an early feature of Huntington's disease (HD). We profiled genome-wide interaction sites for the huntingtin protein (HTT) using ChIP-sequencing from mouse striatal tissue at 4 months of age. We include replicate samples from CAG-expanded murine Htt (heterozygous Q111/+) and wildtype littermate controls.

2018-12-01 | GSE102750 | GEO

Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington’s disease

Project description:Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine Huntingtin gene. To study the relationship between peripheral huntingtin levels and striatal HD phenotypes, we utilized a knock-in model of the human HD mutation (the B6.HttQ111/+ mouse). We treated mice with ASOs from 2-10 months of age, a time period over which significant HD-relevant signs progressively develop in the brains of HttQ111/+ mice. Peripheral treatment with ASOs led to persistent reduction of huntingtin protein in peripheral organs, including liver (64% knockdown), brown adipose (66% knockdown), and white adipose tissues (71% knockdown). This reduction was not associated with alterations in the severity of HD-relevant signs in the striatum of HttQ111/+ mice at the end of the study, including transcriptional dysregulation, the accumulation of neuronal intranuclear inclusions, and behavioral changes such as subtle hypoactivity and reduced exploratory drive. These results suggest that the amount of peripheral reduction achieved in the current study does not significantly impact the progression of HD-relevant signs in the central nervous system.

2017-06-12 | GSE97101 | GEO

G3BP1-dependent suppression of polyglutamine aggregation in Huntington’s models and its failure upon stress granule formation

Project description:To define the interactome of huntingtin protein (HTT) in human neurons, we assessed interactors of HTT with coimmunoprecipitation experiments with huntingtin antibody or polyqlutamine antibody (it only recognizes mutant huntingtin protein with abnormal polyqlutamine expansion) in striatal neurons differentiated from control and patient-derived iPSC lines (HD-iPSCs). GFP antibody used as a negative control.

2022-12-02 | PXD037618 | Pride

Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Project description:Transcriptional dysregulation in Huntington’s disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-seq in an in vitro HD model to investigate the effects of mutant huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes, whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at single-cell level and to provide a platform for screening for therapeutics for the disease.

2021-05-05 | GSE171099 | GEO

Experimental replacement therapy counters decreased IGF-1 levels in Huntington’s disease

Project description:Huntington’s disease (HD) is a monogenetic neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) stretch in huntingtin (htt). Here we show that mutant htt reduces the transcription of insulin-like growth factor 1 (IGF-1) and leads to loss of IGF-1 in HD brains, HD mouse models and mutant htt-transgenic microglial cells. IGF-1 replacement therapy by transplantation of genetically engineered mouse neuronal precursor cells (mNPCs) in a mouse model of HD reverted the motor phenotype and countered striatal neuronal loss.

2018-10-01 | GSE19291 | GEO

RNA-Targeting CRISPR/Cas13d System Alleviates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease (Human).

Project description:Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAGEX) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR-Cas13d system (Cas13d/CAGEX) that eliminates toxic CAGEX RNA in HD patient-derived fibroblasts and iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAGEX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained partial reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAGEX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.

2022-11-15 | GSE214108 | GEO

RNA-Targeting CRISPR/Cas13d System Alleviates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease (Mouse).

2022-11-15 | GSE214109 | GEO

Truncation of mutant huntingtin in knock-in mice via CRISPR-Cas9 uncovers exon1 huntingtin as a key pathogenic form

Project description:It remains unknown how polyglutamine expansion in widely expressed proteins can cause selective neurodegeneration. In Huntington’s disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Considerable efforts have been devoted to investigating how HTT is cleaved and whether blocking its cleavage is therapeutically beneficial. However, using CRISPR-Cas9 to truncate full-length mutant Htt in HD140Q knock-in (KI) mice, we found that exon1 Htt is stably present in the brain, regardless of truncation sites in full-length Htt. This N-terminal Htt led to similar HD phenotypes and age-dependent Htt accumulation in striatum in different KI mice. Exon1 Htt is constantly generated but its selective accumulation in the striatum is caused by the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function accounts for the selective neuropathology in HD and highlight therapeutic importance in regulating this function.

2020-04-21 | GSE145879 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data