The transcriptional modulator H2AFY marks Huntington's disease activity in men and mice
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE24250 | GEO | 2011/09/01
SECONDARY ACCESSION(S): PRJNA133053
REPOSITORIES: GEO
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Project description:To accelerate the development of disease-modifying therapeutics for Huntington’s disease (HD), a dynamic biomarker of disease activity and treatment response is critically needed. Venous cellular whole blood from 8 patients with Huntington's disease (HD) and 6 control subjects were collected in PAXgene tubes (Wiagen, Valencia, CA). RNA was isolated from whole blood using the PAXgene blood RNA kit (Qiagene) with DNase treatment. The biotinylated complementary RNA was fragmented and hybridized to Affymetrix human genome U133A microarrays. The Affymetrix .CEL files were normalized to “all probe sets” in a standardized matter, and scaled to 100 by the MAS5 5.0 algorithm implemented in the Bioconductor package.
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Project description:Transcriptional dysregulation is well documented in Huntington’s disease (HD) post-mortem brain. We previously identified gene expression profiles from both symptomatic and asymptomatic HD prefrontal cortex which characterize the effects of degeneration in disease versus normal brains. Transcriptional dysregulation in HD brain is well documented by these studies and others, but the extent and causes of this dysregulation remain unknown. Here, we present a large ribo-depleted RNA sequencing (rdRNA-Seq) dataset and novel bioinformatic methodology to further characterize transcriptional dysregulation in HD brain as it relates to disease variables, including CAG repeat size, age of symptom onset, and rate of neurodegeneration.
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Project description:Long-term implantation of human NSCs in Huntington’s disease (HD) mice ameliorates behavioral deficits and reduces mutant Huntingtin accumulation. The human NSCs survive and differentiate into diverse neuronal populations, form connections, improve synaptic properties and show restoration of several transcriptional changes in HD mouse cells.
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Project description:Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the CAG expansion in the Huntingtin (HTT) gene. Several studies have shown the potential of microRNAs as biomarkers in neurodegenerative diseases. However, no bona fide microRNAs have been identified as promising diagnostic biomarkers for HD. As part of the PREDICT-HD project, here we performed NanoString on blood samples of 115 pre-manifest HD cases and 111 controls in an effort to provide promising biomarkers for the diagnostic of HD or the disease processes tracking. The results showed that five miRNAs (miR-1252, miR-433, miR-553, miR-138-5p and miR-2053) are significantly differentially expressed in pre-manifest gene-positive HD cases vs. gene-negative controls. We also explored the miRNAs associated with HD severity by correlating the miRNA expression with CAP scores of 115 pre-manifest HD samples and found that 41 and 24 miRNAs are negatively and positively correlated with CAP scores significantly. Furthermore, target gene set of miR-138 and miR-433 , its co-expressed mRNAs in ROSMAP, and differentially expressed mRNAs of HD reveal four overlap genes (CASP7, CNOT6L, TMED and FERMT2). In summary, our study provides new insights into biomarker of Huntington’s disease by analyzing the cross-sectional miRNA expression data in blood.
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Project description:Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the CAG expansion in the Huntingtin (HTT) gene. Several studies have shown the potential of microRNAs as biomarkers in neurodegenerative diseases. However, no bona fide microRNAs have been identified as promising diagnostic biomarkers for HD. As part of the PREDICT-HD project, here we performed NanoString on blood samples of 115 pre-manifest HD cases and 111 controls in an effort to provide promising biomarkers for the diagnostic of HD or the disease processes tracking. The results showed that five miRNAs (miR-1252, miR-433, miR-553, miR-138-5p and miR-2053) are significantly differentially expressed in pre-manifest gene-positive HD cases vs. gene-negative controls. We also explored the miRNAs associated with HD severity by correlating the miRNA expression with CAP scores of 115 pre-manifest HD samples and found that 41 and 24 miRNAs are negatively and positively correlated with CAP scores significantly. Furthermore, target gene set of miR-138 and miR-433 , its co-expressed mRNAs in ROSMAP, and differentially expressed mRNAs of HD reveal four overlap genes (CASP7, CNOT6L, TMED and FERMT2). In summary, our study provides new insights into biomarker of Huntington’s disease by analyzing the cross-sectional miRNA expression data in blood.
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Project description:Gene expression profiling of purified medium spiny neurons (MSNs) in R6/2 Huntington’s disease (HD) model mouse. To purify MSNs by FACS, R6/2 was crossed with Scn4b-Venus transgenic mouse expressing Venus in MSNs. MSN gene set excluded gene expression alterations in other neuronal populations, indicating the gene set displays MSN-specific pathological changes in HD. We identified the dysregulated genes expression, which are associated with apoptosis and transcriptional regulation, and found considerable number of disease causative genes in MSN gene set.
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Project description:Transcriptional changes occur presymptomatically and throughout Huntington’s disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome-scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and CAG repeat length-dependent gene expression changes in Htt CAG knock-in mouse striatum, and replicated many of these associations in independent transcriptomic and proteomic datasets. 13 of 48 of these predicted TF-target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found CAG repeat length-dependent changes in the genomic occupancy of SMAD3 and confirmed our model’s prediction that many SMAD3 target genes are down-regulated early in HD.
2018-02-01 | GSE88775 | GEO
Project description:Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the gene encoding Huntingtin (HTT). Transcriptome dysregulation is a major feature of HD pathogenesis, as revealed by a large body of work on gene expression profiling of tissues from human HD patients and mouse models. These studies were primarily focused on transcriptional changes affecting steady-state overall gene expression levels using microarray based approaches. A major missing component however has been the study of transcriptome changes at the post-transcriptional level, such as alternative splicing. Alternative splicing is a critical mechanism for expanding regulatory and functional diversity from a limited number of genes, and is particularly complex in the mammalian brain. Here we carried out a deep RNA-seq analysis of 7 human HD brains and 7 controls to systematically discover aberrant alternative splicing events and characterize potential associated splicing factors in HD. We identified 593 differential alternative splicing events between HD and control brains. Using an expanded panel of 54 brain tissues from patients and controls, we also identified 9 splicing factors exhibiting significantly altered expression levels in HD patient brains. Moreover, follow-up molecular analyses of one splicing factor PTBP1 revealed its impact on disease-associated splicing patterns in HD. Collectively, our data provide genomic evidence for widespread splicing dysregulation in HD brains, and suggest the role of aberrant alternative splicing in the pathogenesis of HD
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Project description:Direct neuronal conversion of fibroblasts from Huntington’s disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD.
2022-09-15 | GSE194241 | GEO