Huntingtin loss-of-function contributes to transcriptional deregulation in Huntington’s disease (miRNA-Seq)
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ABSTRACT:
PROVIDER: PRJNA1126696 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29493429_1.fastq.gz | Fastqsanger.gz | |||
| SRR29493429_2.fastq.gz | Fastqsanger.gz | |||
| SRR29493430_1.fastq.gz | Fastqsanger.gz | |||
| SRR29493430_2.fastq.gz | Fastqsanger.gz | |||
| SRR29493431_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Huntingtin loss-of-function contributes to transcriptional deregulation in Huntington’s disease (RNA-Seq)
| PRJNA1126697 | ENA
Project description:Huntington’s disease (HD) is a fatal neurodegenerative disorder that is caused by the expansion of CAG repeats in the HTT gene, which results in a long polyglutamine (polyQ) tract in the huntingtin protein (HTT). In this study, we searched for networks of deregulated RNAs that contribute to initial transcriptional changes in HD neuronal cells and HTT-deficient cells. We used RNA-seq (including small RNA sequencing) to analyze a set of isogenic, human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs); and we observed numerous changes in gene expression and substantial dysregulation of miRNA expression in HD and HTT-knockout (HTT-KO) cell lines. The gene set that was upregulated in both HD and HTT-KO cells was enriched in genes that are associated with DNA binding and regulation of transcription. For both of these models, we confirmed the substantial upregulation of the transcription factors (TFs) TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2 and FOXD1 in NSCs and medium spiny neuron (MSN)-like cells. Moreover, we identified miRNAs that were consistently deregulated in HD and HTT-KO NSCs and MSN-like cells, including miR-214, miR-199, and miR-9. We suggest that these miRNAs function in the network that regulates TWIST1 and HTT expression via regulatory feed-forward loop (FFL) in HD. Additionally, we reported that the expression of selected TFs and miRNAs tended to progressively change during the neural differentiation of HD cells, what was not observed in HTT-KO model. Based on comparing the HD and HTT-KO cell lines, we propose that early transcriptional deregulation in HD is largely caused by loss of HTT function.
2024-06-27 | GSE270473 | GEO
Project description:Huntington’s disease (HD) is a fatal neurodegenerative disorder that is caused by the expansion of CAG repeats in the HTT gene, which results in a long polyglutamine (polyQ) tract in the huntingtin protein (HTT). In this study, we searched for networks of deregulated RNAs that contribute to initial transcriptional changes in HD neuronal cells and HTT-deficient cells. We used RNA-seq (including small RNA sequencing) to analyze a set of isogenic, human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs); and we observed numerous changes in gene expression and substantial dysregulation of miRNA expression in HD and HTT-knockout (HTT-KO) cell lines. The gene set that was upregulated in both HD and HTT-KO cells was enriched in genes that are associated with DNA binding and regulation of transcription. For both of these models, we confirmed the substantial upregulation of the transcription factors (TFs) TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2 and FOXD1 in NSCs and medium spiny neuron (MSN)-like cells. Moreover, we identified miRNAs that were consistently deregulated in HD and HTT-KO NSCs and MSN-like cells, including miR-214, miR-199, and miR-9. We suggest that these miRNAs function in the network that regulates TWIST1 and HTT expression via regulatory feed-forward loop (FFL) in HD. Additionally, we reported that the expression of selected TFs and miRNAs tended to progressively change during the neural differentiation of HD cells, what was not observed in HTT-KO model. Based on comparing the HD and HTT-KO cell lines, we propose that early transcriptional deregulation in HD is largely caused by loss of HTT function.
2024-06-27 | GSE270472 | GEO
Project description:Huntington’s disease is caused by a polyglutamine repeat expansion at the N-terminus of the huntingtin protein which affects the function and folding of the protein, and results in intracellular protein aggregates. Here, we examined whether this mutation leads to altered ubiquitination of huntingtin and other proteins in both soluble and insoluble fractions of brain lysates of the Q175 knock-in Huntington disease mouse model and the Q20 wild-type mouse model. Ubiquitination sites are detected by identification of Gly-Gly (diGly) remnant motifs that remain on modified lysine residues after digestion. We identified K6, K9, K132, K804 and K837 as endogenous ubiquitination sites of soluble huntingtin, with wild-type huntingtin being mainly ubiquitinated at K132, K804 and K837. Mutant huntingtin protein levels were strongly reduced in the soluble fraction while K6 and K9 were mainly ubiquitinated. In the insoluble fraction increased levels of huntingtin K6 and K9 diGly sites were observed for mutant huntingtin as compared to wild type. Besides huntingtin, proteins with various roles, including membrane organization, transport, mRNA processing, gene transcription, translation, catabolic processes and oxidative phosphorylation, were differently expressed or ubiquitinated in wild-type and mutant huntingtin brain tissues. Correlating protein and diGly site fold-changes in the soluble fraction revealed that diGly site abundances of the majority of the proteins were not related to protein fold-changes, indicating that these proteins were differentially ubiquitinated in the Q175 mice. In contrast, both the fold-change of the protein level and diGly site level were increased for several proteins in the insoluble fraction, including ubiquitin, ubiquilin-2, sequestosome-1/p62 and myo5a. Our data sheds light on putative novel proteins involved in different cellular processes as well as their ubiquitination status in Huntington’s disease, which forms the basis for further mechanistic studies to understand the role of differential ubiquitination of huntingtin as well as ubiquitin-regulated processes in Huntington’s disease.
2019-06-05 | PXD010161 | Pride
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
Project description:Huntingtin protein, mutated in Huntington disease, is implicated in nucleic acid- mediated processes, yet evidence for direct huntingtin-nucleic acid interaction is limited. Here we show wildtype and mutant huntingtin co-purify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wildtype and mutant huntingtin revealed NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington’s disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin co-localized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a novel huntingtin interactor, demonstrating huntingtin’s involvement in RNA-mediated functions and paraspeckle regulation.
2024-12-31 | GSE267435 | GEO
Project description:Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering
| PRJNA872520 | ENA
Project description:The earliest stages of Huntington’s disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin protein (HTT). To explore the hypothesis DNA methylation may be altered in cells expressing mutated HTT, we use reduced-representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in expression in the presence of mutant huntingtin demonstrate significant changes in DNA methylation. Regions with low CpG content, which have previously been shown to undergo methylation changes in response to neuronal activity, are disproportionately affected. Based on the sequence of regions that change in methylation, we identify AP-1 and SOX2 as transcriptional regulators associated with DNA methylation changes, and we confirm these hypotheses using genome-wide chromatin immunoprecipitation (ChIP-Seq). Our findings suggest new mechanisms for the effects of polyglutamine-expanded HTT. These results also raise important questions about the potential effects of changes in DNA methylation on neurogenesis and at later stages, cognitive decline in Huntington’s patients. RRBS in STHdhQ7/Q7 and STHdhQ111/Q111 cells
2013-01-24 | E-GEOD-43432 | biostudies-arrayexpress
Project description:Huntington’s disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms. Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons under defined culture conditions. Analysis of differentially expressed genes between Huntington’s disease and wild type iPSCs derived GABA MS-like neurons has been performed.
2016-02-04 | GSE77558 | GEO
Project description:The earliest stages of Huntington’s disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin protein (HTT). To explore the hypothesis DNA methylation may be altered in cells expressing mutated HTT, we use reduced-representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in expression in the presence of mutant huntingtin demonstrate significant changes in DNA methylation. Regions with low CpG content, which have previously been shown to undergo methylation changes in response to neuronal activity, are disproportionately affected. Based on the sequence of regions that change in methylation, we identify AP-1 and SOX2 as transcriptional regulators associated with DNA methylation changes, and we confirm these hypotheses using genome-wide chromatin immunoprecipitation (ChIP-Seq). Our findings suggest new mechanisms for the effects of polyglutamine-expanded HTT. These results also raise important questions about the potential effects of changes in DNA methylation on neurogenesis and at later stages, cognitive decline in Huntington’s patients. mRNA-seq in STHdhQ7/Q7 and STHdhQ111/Q111 cells
2013-01-24 | E-GEOD-43431 | biostudies-arrayexpress