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

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

PROVIDER: PRJNA937615 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23582375.fastq.gz	Fastqsanger.gz
	SRR23582376.fastq.gz	Fastqsanger.gz
	SRR23582377.fastq.gz	Fastqsanger.gz
	SRR23582378.fastq.gz	Fastqsanger.gz
	SRR23582379.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

Project description:Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice

| PRJNA937611 | ENA

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

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

| PRJNA937617 | ENA

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-20 | GSE225790 | GEO

siRNA profiling of Zebrafish embryos knocked down for Spt5

Project description:The Spt4-Spt5 complex, and its human homolog DSIF (DRB sensitivity-inducing factor), is unique in its ability to regulate Pol II processivity. Previous studies have shown that Spt5 has the characteristics of a general transcription-elongation factor. However, mutagenesis of Spt5 showed specific phenotypes during development, which were far less severe than those of Pol II defects or TBP deficient embryos. It seems paradoxical that a mutation which alters a general elongation factor can cause rather specific developmental defects. By using Spt5 knockdown zebrafish embryos and microarrays, here we showed that transcript abundance for only a small subset of genes is altered by loss of Spt5. Further investigation of the down-regulated genes showed that the genes most intensely repressed by the knockdown were strongly activated during early development in untreated embryos. Thus, this study shows that gene activation levels may create different requirements for Pol II processivity. Active transcription requires Spt5 for efficient elongation through its stimulatory activity on Pol II processivity. Experiment Overall Design: The expression pattern of Spt5 knockdown embryos was compared to that of the control mopholino oligo injected embryos, both at 21 hours post-fertilization, to show the targets of Spt5. The activation levels of the Spt5-knockdown affected genes were measured by compareing the abundance of transcripts in 21 hours post-fertilization untreated embryos to that in 5 hours post-fertilization untreated embryos.

2008-06-14 | E-GEOD-6127 | biostudies-arrayexpress

Analysis of differentially expressed genes between Huntington’s disease and control iPSCs derived GABA MS-like neurons

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

The expression of Spt5 targeted genes

Project description:The Spt4-Spt5 complex, and its human homolog DSIF (DRB sensitivity-inducing factor), is unique in its ability to regulate Pol II processivity. Previous studies have shown that Spt5 has the characteristics of a general transcription-elongation factor. However, mutagenesis of Spt5 showed specific phenotypes during development, which were far less severe than those of Pol II defects or TBP deficient embryos. It seems paradoxical that a mutation which alters a general elongation factor can cause rather specific developmental defects. By using Spt5 knockdown zebrafish embryos and microarrays, here we showed that transcript abundance for only a small subset of genes is altered by loss of Spt5. Further investigation of the down-regulated genes showed that the genes most intensely repressed by the knockdown were strongly activated during early development in untreated embryos. Thus, this study shows that gene activation levels may create different requirements for Pol II processivity. Active transcription requires Spt5 for efficient elongation through its stimulatory activity on Pol II processivity. Keywords: Spt5, microarray analysis, development, transcription, transcription elongation

2007-10-25 | GSE6127 | GEO

Genome wide localization of Activation induced cytidine deaminase (AID), Spt5, and RNA Polymerase II (PolII) in mouse

Project description:Activation induced cytidine deaminase (AID) initiates antibody gene diversification by creating U:G mismatches. However, AID is not specific for antibody genes. Off-target lesions can activate oncogenes or cause chromosome translocations. Despite its importance in these key transactions little is known about how AID finds its target sites. To examine AID regulation we performed an shRNA screen. We found that Spt5, a factor associated with paused RNA polymerase II (Pol II) and single stranded DNA (ssDNA), is required for class switch recombination (CSR). Spt5 interacts with AID, it is required for the association of AID and Pol II, and for AID recruitment to switch regions. ChIP-seq experiments reveal that Spt5 co-localizes with AID and stalled Pol II. Further, Spt5 accumulation at sites of Pol II pausing is predictive of AID-induced mutation. Our data suggest that Spt5 acts as an adaptor, which brings AID to Pol II on target DNA. PolII, AID, and Spt5 were immunoprecipitated from in vitro activated B cells. For Spt5 and AID, two different antibodies were used in separate, biological replicates

2010-10-05 | E-GEOD-24178 | biostudies-arrayexpress

LEDGF/p75 promotes transcriptional pausing through preventing SPT5 phosphorylation

Project description:The transcriptional progression is regulated by SPT5, which is involved in both promoter-proximal RNA polymerase II (Pol II) pausing and elongation, which serve as rate-limiting steps in metazoan. However, the mechanism for SPT5 coordinating these processes remains unclear. Here we report that the disordered sub-regions within SPT5 contain a prion-like domain (PLD) that is required for Pol II pausing, while the phosphorylation site-rich domain (PRD) is essential for transcript elongation. Mechanically, SPT5-PLD helps stabilize Pol II pausing by preventing SPT5-PRD phosphorylation mediated by the super elongation complex (SEC). SPT5-PLD also maintains Pol II pausing by recruiting a newly identified transcriptional pause regulator, PSIP1, which inhibits phosphorylation required for elongation. Additionally, SPT5-PLD prevents premature release of Pol II pausing through PSIP1’s IBD domain by counteracting SEC. Our results demonstrate that SPT5 possesses intrinsic characteristics that balance the transcriptional process by preventing premature pause release and promoting progression to elongation.

2025-01-08 | GSE250380 | GEO

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