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SRP158328
Homo sapiens
6 Downloadable Samples
Description
RNA polymerase III (Pol III) is an essential enzyme responsible for the synthesis of several small non-coding RNAs, a number of which are involved in mRNA translation. Recessive mutations in POLR3A, encoding the largest subunit of Pol III, cause POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), characterized by deficient central nervous system myelination. Identification of the downstream effectors of pathogenic POLR3A mutations has been so far elusive. Here, we used CRISPR-Cas9 to introduce the POLR3A mutation c.2554A>G (p.M852V) into human cell lines and assessed its impact on Pol III biogenesis, nuclear import, DNA occupancy, transcription, and protein levels. Transcriptomic profiling uncovered a subset of transcripts vulnerable to Pol III hypofunction, including a global reduction in tRNA levels. The brain cytoplasmic BC200 RNA (BCYRN1), involved in translation regulation, was consistently affected in all our cellular models, including patient-derived fibroblasts. Genomic BC200 deletion in an oligodendroglial cell line led to major transcriptomic and proteomic changes, having a larger impact than those of POLR3A mutations. Upon differentiation, mRNA levels of the MBP gene, encoding myelin basic protein, were significantly decreased in POLR3A-mutant cells. Our findings provide the first evidence for impaired Pol III transcription in cellular models of POLR3-HLD and identify several candidate effectors, including BC200 RNA, having a potential role in oligodendrocyte biology and involvement in the disease. Overall design: Gene expression profiling of Pol III transcripts in control and POLR3A-mutated cell lines (HEK293 and MO3.13) using RNA-seq and small RNA-seq; ChIP-seq of FLAG-tagged POLR3A-WT and mutated POLR3A-M852V
Publication Title
Leukodystrophy-associated <i>POLR3A</i> mutations down-regulate the RNA polymerase III transcript and important regulatory RNA <i>BC200</i>.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked monogenic disease associating severe learning deficit andassociated to typical facial and digital abnormalities and skeletal changes. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized.
Publication Title
RSK2 is a modulator of craniofacial development.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 18 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip (gene symbol), Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
Publication Title
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
Publication Title
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
Publication Title
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
1. To identify potential effectors responsible for anti-tumorigenesis by targeting PLD1, we performed microarray in two Wnt-relevant colon cancer cells and analyzed transcriptional profile of genes that were differently expressed by inhibition and knockdown of PLD1
Publication Title
Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 29 Downloadable Samples
- Illumina HiSeq 2000
Description
Memory stabilization after learning requires transcriptional and translational regulations in the brain, yet the temporal molecular changes following learning have not been explored at the genomic scale. We here employed ribosome profiling and RNA sequencing to quantify the translational status and transcript levels in mouse hippocampus following contextual fear conditioning. We identified 104 genes that are dynamically regulated. Intriguingly, our analysis revealed novel repressive regulations in the hippocampus: translational suppression of ribosomal protein-coding genes at basal state; learning-induced early translational repression of specific genes; and late persistent suppression of a subset of genes via inhibition of ESR1/ERa signaling. Further behavioral analyses revealed that Nrsn1, one of the newly identified genes undergoing rapid translational repression, can act as a memory suppressor gene. This study unveils the yet unappreciated importance of gene repression mechanisms in memory formation. Overall design: The application of ribosome profiling and RNA-seq techniques to mouse hippocampi tissues after contextual fear conditioning and to mouse hippocampal primary cultures. Mouse ESCs were also examined.
Publication Title
Multiple repressive mechanisms in the hippocampus during memory formation.
Sample Metadata Fields
No sample metadata fields
View Samples- Arabidopsis thaliana
- 25 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
In Arabidopsis, jasmonate is required for stamen and pollen maturation. Mutants deficient in jasmonate synthesis, such as opr3, are male-sterile but become fertile when jasmonate is applied to developing flower buds. We have used ATH1 oligonucleotide arrays to follow gene expression in opr3 stamens for 22 hours following jasmonate treatment. In these experiments, a total of 821 genes were specifically induced by jasmonate and 480 repressed. Comparisons with data from previous studies indicate that these genes constitute a stamen-specific jasmonate transcriptome, with a large proportion (70%) of the genes expressed in the sporophytic tissue but not in the pollen. Bioinformatics tools allowed us to associate many of the induced genes with metabolic pathways that are likely up-regulated during jasmonate-induced maturation. Our pathway analysis led to the identification of specific genes within larger families of homologues that apparently encode stamen-specific isozymes. Extensive additional analysis of our dataset identified 13 transcription factors that may be key regulators of the stamen maturation processes triggered by jasmonate. Two of these transcription factors, MYB21 and MYB24, are the only members of subgroup 19 of the R2R3 family of MYB proteins. A myb21 mutant obtained by reverse genetics exhibited shorter anther filaments, delayed anther dehiscence and greatly reduced male fertility. A myb24 mutant was phenotypically wild type, but production of a myb21myb24 double mutant indicated that introduction of the myb24 mutation exacerbated all three aspects of the myb21 phenotype. Exogenous jasmonate could not restore fertility to myb21 or myb21myb24 mutant plants. Together with the data from transcriptional profiling, these results indicate that MYB21 and MYB24 are induced by jasmonate and mediate important aspects of the jasmonate response during stamen development.
Publication Title
Transcriptional regulators of stamen development in Arabidopsis identified by transcriptional profiling.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
To explore the function of NFAT5 in macrophage, we performed transcriptome analysis in raw cells.
Publication Title
Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis.
Sample Metadata Fields
Specimen part, Cell line
View Samples