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Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 24h]

ABSTRACT: We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. We determined the global effect of short and long-term SPI-21 treatment by RNA-seq and compared the affected genes between the two treatments. The results revealed that temporary and constitutive Spt5-regulated genes can be distinguished by SPIs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136023 | GEO | 2019/10/01

REPOSITORIES: GEO

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Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 2h]

Project description:We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. We determined the global effect of short and long-term SPI-21 treatment by RNA-seq and compared the affected genes between the two treatments. The results revealed that temporary and constitutive Spt5-regulated genes can be distinguished by SPIs.

2019-10-01 | GSE136022 | GEO

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [GRO-Seq]

Project description:We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. Using SPIs we identified Spt5 target genes that responded with profoundly diverse kinetics and a novel regulatory element of proximal-promoter-pausing. To obtain a genome-wide view of the impact of SPIs on transcription, we performed Global run-on sequencing (GRO-seq) using nuclei of HeLa cells treated with either DMSO (control) or SPI-21.

2019-10-01 | GSE136024 | GEO

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [4sU-seq]

Project description:We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. Using SPIs we identified Spt5 target genes that responded with profoundly diverse kinetics and a novel regulatory element of proximal-promoter-pausing. To validate that the effects of SPIs are at the transcriptional level, cellular RNA was metabolically labeled with 4-thio-uridine (4sU) for 2 hours in the presence of DMSO or SPI-21 in the presence or absence of TNFα. Newly synthesized labeled RNA was then purified and subjected to RNA-seq.

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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]

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Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 24h]

Project description:Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 24h]

| PRJNA560965 | ENA

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [4sU-seq]

Project description:Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [4sU-seq]

| PRJNA560967 | ENA

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [GRO-Seq]

Project description:Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [GRO-Seq]

| PRJNA560966 | ENA

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

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 2h]

Project description:Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 2h]

| PRJNA560964 | ENA