Expression data of hypothalamus from the BACHD and HTT overexpression mouse models of Huntington's disease (HD)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE215217 | GEO | 2022/10/18
REPOSITORIES: GEO
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Project description:To study cell type- and HTT CAG length-dependent transcriptional and alternative splicing changes associated with HD, we conducted deep RNA-sequencing analysis on human embryonic stem cells (hESC), NPC and neuron cell lines (ESC and NPC, NEU) expressing wild-type (27/ and 30 CAG repeats), 45 CAG (45Q; representing 45 polyQ mutant HTT protein) and 81 CAG (81Q) repeat expansion HTT gene (n=3). The cell lines were derived from an isogenic HTT CAG repeat expansion allelic cell line panel (IsoHD) where hESC H9 cells were genetically modified with monoallelic knockin of expanded CAG tract in exon 1 of HTT representing early onset (45Q) and late onset (81Q) HD, with the 27Q/30Q genotype as healthy control phenotype (Ooi et al., 2019). The sequencing experiment generated 2.9 billion pairs of 150 bp paired-end reads from 27 samples (3 clones, 3 genotypes, 3 cell lines), with 80 to 110 million read pairs per sample. Transcriptome alignment yielded 75 to 100 million uniquely mapped read pairs across all samples.
2024-09-17 | GSE217469 | GEO
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.
2013-05-03 | E-GEOD-34721 | biostudies-arrayexpress
Project description:We generated two types of DNA methylation datasets (Reduced Representation Bisulfite Sequencing [RRBS] and custom methylation array) from a heterozygous HD knock-in mouse model. The heterozygous Htt knock-in line expressed one wildtype endogenous Htt allele and a second Htt allele with knock-in of human mHTT exon 1 with either approximately 190 CAG repeats (Q175) or 20 CAG repeats (Q20). For each genotype (Q175 and Q20) we analyzed two brain regions (striatum and cerebellum) from 8 mice each on the RRBS platform (N=32 RRBS samples). Our EWAS of mutant Htt gene status (i.e. Q175 status) across the two brain regions identified two genome-wide significant CpGs in Htt region. contributor: CHDI foundation
2020-07-02 | GSE147156 | GEO
Project description:In Huntington’s Disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed towards wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.
2023-12-01 | GSE239312 | GEO
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion.
2013-05-03 | GSE34721 | GEO
Project description:Huntington’s Disease is a neurodegenerative disorder caused by a CAG expansion in exon1 of the huntingtin (Htt) gene. The resulting polyglutamine expansion in the ubiquitously expressed mutant Htt (mHtt) protein leads to selective neurodegeneration. In this study we set out to identify interacting proteins of full length wild-type and mHtt protein in the mice cortex brain region in order to get a better understanding of the processes involved in HD pathology.
2021-06-21 | PXD024254 | Pride
Project description:Huntington’s disease (HD) is caused by CAG repeat expansion at the N-terminal region of huntingtin (HTT) gene and characterize by neuronal cell loss and neuroinflammation transcriptional profile change in striatum, cortex and other brain regions. Here we reported generation and characterization of BAC-CAG, a novel full length human HD mouse model host over 120 uninterrupted CAG repeats. we performed RNA-seq analysis of the striatum and cortex of BAC-CAG mice at 2m, 6m and 12m of age (N=6 per genotype, sex balanced). We observed an age-dependent transcriptionopathy in the striatum of BAC-CAG mice, with only 7 and 36 significant DE genes in 2m and 6m striatum respectively (FDR<0.1), but 820 DE genes (538 downregulated and 282 upregulated genes) at 12m of age (FDR<0.1). The transcriptomic deficits in this model are highly striatum-selective, as we only detected 4, 3 and 14 DE genes (FDR<0.1) at 2m, 6m and 12m respectively in BAC-CAG cortices compared to WT controls. Remarkably, we found a highly significant positive transcriptome-wide correlation (r=0.62) of DE Z statistics between BAC-CAG vs WT at 12m and Q140 vs WT at 6m (p<1e-200). This result demonstrates a high concordance of both upregulated and downregulated genes in the BAC-CAG striatum compared to that of allelic series KI mice; but RNA-seq studies of BACHD mice at 12m and found only 50 genes significantly differentially expressed (DE) genes (FDR<0.1) in the striatum at 12m of age compared to WT littermates, 31 downregulated and 19 upregulated genes. In the cortex at 12m of age, BACHD only showed 6 significantly downregulated genes and 7 upregulated genes comapred to WT controls (FDR<0.1).
2022-02-02 | GSE153827 | GEO
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 6 month old knock-in mice with CAG lengths of 175 along with littermate control wild-type animals. mRNA expression profiles were obtained via RNA-seq analysis performed on samples from the Brown Adipose tissue, White Adipose tissue around Gonad, White Adipose tissue around Intestine, Brain - Brainstem, Brain - Cerebellum, Brain - Hippocampus, Brain - Hypothalamus/Thalamus, Corpus callosum, Gastrocnemius, Heart, and Skin of 6 month old knock-in mice with CAG lengths of 175 along with littermate control wild-type animals.
2016-02-15 | E-GEOD-65775 | biostudies-arrayexpress
Project description:Expression data of hypothalamus from the BACHD and HTT overexpression mouse models of Huntington's disease (HD)
| PRJNA889377 | ENA
Project description:Aims: While Huntingtonâs disease is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. Methods and Results: The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3mo of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol challenge; however, the treatment exacerbated fibrotic lesions in the heart. Gene expression analysis indicates a strong tilt toward apoptosis in the young mutant tissue as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the largest changes occurring in the cardiovascular disease and cellular metabolism clusters. Conclusions: The BACHD model of HD exhibit a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher CV risk in HD. These changes are consistent with dysfunction in ANS regulation although the hearts did respond adaptively to β-adrenergic challenge. Gene expression pattern changes are subtle but suggests biomarkers focusing on apoptosis, metabolism, immune function are worth further exploration. Microarray-based gene expression analysis in tissue from transgenic mice and controls at different ages
2016-03-01 | E-GEOD-76593 | biostudies-arrayexpress