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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
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
In this study we determine the transcriptional profile by RNAseq of mESC in the absence of Smad1 and Smad5 and in subpopulation of mESC with different levels of BMP-SMAD activation. Overall design: Transcriptome analysis using RNAseq was performed on 3 biological replicates of BRE negative and positive mESC subpopulations, which were collected in pairs at 3 different times. Transcriptome analysis using RNAseq was performed on Smad1/5 floxed (FL) and knockout (KO) mESC. Two different parental cell lines were used. For each parental cell line we analyzed one Smad1/5 FL sample and two Smad1/5 KO samples, resulting in respectively two and four biological replicates for the FL and KO conditions.
Publication Title
BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Hordeum vulgare
- 24 Downloadable Samples
Affymetrix Barley Genome Array (barley1)
Description
The photosynthetic organs of the barley spike (lemma, palea and awn) are resistant to drought. This is a beneficial trait because they can sustain grain-filling when drought occurs at the reproductive stage. There is little information about gene expression in the spike organs under drought conditions. In this study, we compared gene expression in drought-stressed lemma, palea, awn and seed at the grain-filling stage using the Barley1 Genome Array in order to identify drought-regulated organ-specific genes.
Publication Title
Drought response in the spikes of barley: gene expression in the lemma, palea, awn, and seed.
Sample Metadata Fields
Specimen part, Treatment
View Samples
SRP001455- Caenorhabditis elegans
- 20 Downloadable Samples
- Illumina Genome Analyzer
Description
High throughput sequencing to derive function of cde-1 in endogenous RNAi in C. elegans Overall design: Small RNAs were cloned from C. elegans adults, following removal of tri-phosphate groups from 5'' end. Sequencing was performed using the Illumina 1G platform.
Publication Title
CDE-1 affects chromosome segregation through uridylation of CSR-1-bound siRNAs.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In this experiment we are exploring which genes are regulated by TRIM24 in androgen-dependent and castration-resistant prostate cancer cells.
Publication Title
TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome. Overall design: mRNA-Seq profiling of 9 2N and 8 DS human fibroblasts samples of age 5 months (< 1 year) and 2 years. These samples come from 5 unrelated 2N individuals (of which 2 individuals, one each of 5 months and 2 years, have 3 replicates each) and 3 unrelated DS individuals (of which 2 individuals, one each of 5 months and 2 years, have 3 replicates each). Five samples were reanalyzed from GSE55504.
Publication Title
mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Homo sapiens
- 22 Downloadable Samples
Description
Cancer evolution is fueled by genetic and epigenetic diversity, and intra-tumoral heterogeneity in DNA methylation has been shown to co-operate with genetic heterogeneity to empower evolutionary capacity of cancers such as chronic lymphocytic leukemia. Here, we show that epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging epigenetic identities. This manifests in incomplete gene silencing by the Polycomb complex, unexpected co-occurrence of typically mutually exclusive activating and repressing histone modifications, and greater cell-to-cell transcriptional heterogeneity. Overall design: Given the importance of histone modifications to lineage plasticity in cancer15-17, intra-leukemic epigenetic heterogeneity may extend to histone modifications, likely promoting lineage plasticity by enabling permissive chromatin states. To address this question, we complemented DNAme analysis with a chromatin immunoprecipitation sequencing (ChIP-seq) compendium of histone post-translational modifications (H3K4me3, H3K27ac, H3K4me1, H3K27me3, H3K9me3 and H3K36me3) and transcriptome sequencing (RNA-seq) in a cohort of primary CLL and healthy B lymphocytes samples (CLL IGHV unmutated, n = 12; CLL IGHV mutated, n = 10; peripheral blood NBCs [CD23+CD19+CD27-IgD+], peripheral blood memory B cells [GCBs; CD23+CD19+CD27+IgD-], peripheral blood CD20+ cells.
Publication Title
Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Gene expression analysis of Normal CD34+ Cord Blood and UKE1 cell lines treated with hairpins targeting ASXL1.
Publication Title
ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
The MYC transcription factor is a master regulator of diverse cancer pathways and somatic cell reprogramming. MYC is a compelling therapeutic target that exhibits cancer-specific cellular effects. Pharmacologic inhibition of MYC function has proven challenging due to its numerous modes of forced expression and the difficulty of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule bromodomain inhibitors of the BET family of chromatin adaptors. This transcriptional suppression of MYC was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from growth suppression by BET inhibitors and revealed that MYC exerts a direct and tight control of key pro-growth and anti-apoptotic target genes. Transcriptional profiling of two cells after 4 and 8 hours of treatment with BET inhibitor shows that both MYC and its targets are strongly down-regulated. We thus demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and suggest that such inhibitors may have broad clinical applicability given the widespread pathogenetic role of MYC in cancer.
Publication Title
Targeting MYC dependence in cancer by inhibiting BET bromodomains.
Sample Metadata Fields
Cell line, Treatment
View Samples