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SRP075484
Homo sapiens
4 Downloadable Samples
NextSeq 500
Description
Epigenetic regulators have emerged as exciting targets for cancer therapy. Additionally, restoration of antitumor immunity by blocking the PD-L1 signaling using antibodies has proven to be beneficial in cancer therapy. Here we show that BET bromodomain inhibition suppresses PD-L1 expression and restores antitumor immunity in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of antitumor cytotoxic T cells. Together, these data demonstrate an epigenetic approach to block PD-L1 signaling to restore antitumor immunity. Given the fact that BET inhibitors have been proven safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a novel treatment strategy for targeting PD-L1 expression. Overall design: RNA-seq for JQ1 treated and shBRD4 knockdown cells with controls
Publication Title
BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.
Sample Metadata Fields
Treatment, Subject
View Samples- Homo sapiens
- 2 Downloadable Samples
- NextSeq 500
Description
CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in cancers and stimulates growth. However, clinically applicable therapeutic strategies based on CARM1 expression in cancer remains to be explored. Here we show that epithelial ovarian cancer is among the cancers with the highest CARM1 amplification rates that predicates a shorter survival. Our unbiased screen show that CARM1-expressing ovarian cancer cells are selectively sensitive to the inhibition of EZH2, another epigenetic regulator that silences its target genes. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppressed the growth of CARM1-expressing ovarian tumors in two xenograft models. The observed selectivity correlates with upregulation of EZH2 target genes in a CARM1-dependent manner. CARM1 promotes EZH2 dependent gene silencing by methylating BAF155 to alter the antagonism between EZH2 and BAF155. Together, these results indicate that pharmacological inhibition of EZH2 is a novel therapeutic strategy for CARM1-expressing cancers. Overall design: CARM1 wild type and knockout samples assayed by RNA-seq
Publication Title
CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HiSeq 4000
Description
Sequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10 and C18) and parental PEO1 (P1 and P2) cells was performed in order to determine mechanisms of acquired resistance in the resistant cell lines. PEO1 parental cell lines were authenticated prior to sequencing. PEO1 parental were confirmed to be BRCA2-mutated (5139C>G). Olaparib PEO1 resistant cells were generated through a step-wise escalation of olaparib (10nM to 8uM olaparib). In olaparib resistant lines an increase canonical Wnt signaling and loss of of non-canonical Wnt signaling was observed. Overall design: Sequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10, and C18) and parental PEO1 cells was performed in order to determine mecahnisms of acquired resistance.
Publication Title
Activation of Wnt signaling promotes olaparib resistant ovarian cancer.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 5 Downloadable Samples
- NextSeq 500
Description
ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53' apoptotic function by upregulating HDAC6. These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation Overall design: RNA-seq transcription profiling of samples with altered HDAC6 activity
Publication Title
ARID1A-mutated ovarian cancers depend on HDAC6 activity.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 16 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Myeloid progenitors derived from antibiotic-treated mice have cell-intrinsic functional defects. In this microarray dataset, the transcriptomes of bone marrow myeloid progenitors from antibiotic-treated and control mice are compared.
Publication Title
Microbiota-dependent signals are required to sustain TLR-mediated immune responses.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness (CSNB), congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions.
Publication Title
Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Background: Previous studies comparing quantitative proteomics and microarray data have generally found poor correspondence between the two. We hypothesised that this might in part be because the different assays were targeting different parts of the expressed genome and might therefore be subjected to confounding effects from processes such as alternative splicing. Results: Using a genome database as a platform for integration, we combined quantitative protein mass spectrometry with Affymetrix Exon array data at the level of individual exons. We found significantly higher degrees of correlation than have been previously observed (r=0.808). The study was performed using cell lines in equilibrium in order to reduce a major potential source of biological variation, thus allowing the analysis to focus on the data integration methods in order to establish their performance. Conclusion: We conclude that much of the variation observed when integrating microarray and proteomics data may occur as a consequence both of the data analysis and of the high granularity to which studies have until recently been limited. The approach opens up the possibility for the first time of considering combined microarray and proteomics datasets at the level of individual exons and isoforms, important given the high proportion of alternative splicing observed in the human genome.
Publication Title
Exon level integration of proteomics and microarray data.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 15 Downloadable Samples
- Illumina Genome Analyzer II
Description
Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply deep sequencing of RNA 3'' ends ("3-seq") to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed "skin aging") and the impact of broadband light (BBL) treatment. We find that skin aging was associated with the significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became "rejuvenated" after BBL treatment, i.e. more similar in expression level of youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long non-coding RNAs. Skin aging is not associated with systematic changes in 3'' end mRNA processing. Hence, BBL treatment can restore the gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveals a novel set of targets that may lead to new insights into the human skin aging process. Overall design: Examination of broadband light treated and untreated human skin transcriptomes of 5 women aged 50 years or more. They were compared to the skin transcriptomes of 5 young women aged 30 years or less.
Publication Title
Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Samples in this study probe the gene expression kinetics in human CCR6+ Th17 memory T cells activated under Th17 condition. Human CCR6+ Th17 memory T cells were purified from PBMC and gene expression was studied over a time course of 3 days after activation under Th17 condition. RNA from these samples was also profiled using RNA-Seq to compare different transcriptome profiling technologies.
Publication Title
Comparison of RNA-Seq and microarray in transcriptome profiling of activated T cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 180 Downloadable Samples
- Illumina HiSeq 2000
Description
Background: Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. Methods: We performed comprehensive flow-cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Results: Cytometric profiling identified an immunologically “hot” cluster with abundant CD8+ T cells expressing high levels of the PD-1 and TIM-3, and an immunologically “cold” cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function, and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, ~20% of cases had high B cell infiltrates with a subset producing IL-10. Conclusions: Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. Background: Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. Methods: We performed comprehensive flow-cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Results: Cytometric profiling identified an immunologically “hot” cluster with abundant CD8+ T cells expressing high levels of the PD-1 and TIM-3, and an immunologically “cold” cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function, and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, ~20% of cases had high B cell infiltrates with a subset producing IL-10. Conclusions: Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. Overall design: Single-cell comparison of normal and tumor infiltrated B-cells.
Publication Title
Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes.
Sample Metadata Fields
Specimen part, Subject
View Samples