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GSE77194
Mus musculus
3 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Huntington disease (HD) is associated with increased nuclear accumulation of the repressor element-1 silencing transcription factor (REST) which govens a huge gene network. An alternative REST splicing event (E3) eliminates a motif essential for nuclear targeting of REST.
Publication Title
Modulation of nuclear REST by alternative splicing: a potential therapeutic target for Huntington's disease.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 4 Downloadable Samples
Illumina HiSeq 2500
Description
Small molecule curaxin CBL0137 has broad anti-cancer activity in different preclinical models. It interferes with histone-DNA interactions via binding to DNA without causing DNA damage. It resposents first in class "chromatin damaging" agent without genotoxic properties. Its effect on the transcription in human tumor cells was evaluated. DNA-targeting small molecules are widely used for anticancer therapy based on their ability to induce cell death, presumably via DNA damage. DNA in the eukaryotic cell is packed into chromatin, a highly-ordered complex of DNA, histones, and non-histone proteins. These agents perturb chromatin organization. However, the mechanisms, consequences, and impact of the alterations of chromatin structure in relation to their anti-cancer activity is unclear because it is difficult to separate DNA damage and chromatin damage in cells. We recently demonstrated that curaxins, small molecules with broad anticancer activity, bind DNA without causing detectable DNA damage by interfering with histone/DNA interactions and destabilizing the nucleosome. Chromatin unfolding caused by curaxins is sensed by histone chaperone FACT. FACT binds unfolded nucleosomes, which leads to chromatin trapping or c-trapping. In this study, we investigated whether other DNA-targeting small molecules disturb chromatin and cause c-trapping. We found that only compounds directly binding DNA induce chromatin damage and c-trapping. Chromatin damage may occur in the absence of DNA damage and is dependent on the mechanism of compound binding to DNA and its ability to bind chromatinized DNA in cells. We show that FACT is sensitive to a plethora of nucleosomes perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Most importantly, the cytotoxicity of DNA-binding small molecules correlates with their ability to cause chromatin damage , but not DNA damage. Overall design: HT1080 cells were treated with CBL0137 for 1 hour at 1uM. EU was added for the last 15 minutes. Newly synthesized RNA was isolated using Click-iTâ„¢ Nascent RNA Capture Kit (Invitrogen, cat#C10365) according to manufacturer instruction.
Publication Title
Prevention of Chromatin Destabilization by FACT Is Crucial for Malignant Transformation.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 3000
Description
Bulk RNA Sequencing of Healthy Bone Marrow Mononuclear Cells Overall design: Using standard operating procedures, mononuclear cells from bone marrow aspirates were isolated using Ficoll density gradient separation and cryopreserved in 90% FBS/ 10% DMSO for storage in liquid nitrogen. RNA was harvested from thawed cell vials of BMMCs using AllPrep kits (QIAGEN). Libraries were prepared using TruSeq Stranded Total RNA Sample Preparation Kit (Illumina) with 1ug of RNA input. Sequencing was performed by paired-end 75 nt on Illumina HiSeq 3000.
Publication Title
Human bone marrow assessment by single-cell RNA sequencing, mass cytometry, and flow cytometry.
Sample Metadata Fields
Age, Specimen part, Subject
View Samples- Homo sapiens
- 19 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited hit in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry one-hit p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well.
Publication Title
A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Although early developmental processes involve cell fate decisions that define the body axes and establish progenitor cell pools, development does not cease once cells are specified. Instead, most cells undergo specific maturation events where changes in the cell transcriptome ensure that the proper gene products are expressed to carry out unique physiological functions. Pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, establsih organized apical-basal polarity for zymogen granule trafficking, and assemble gap-junctions to perimt efficient cell-cell communication. Despite significant progress in defining transcriptional networks that control initial acinar cell specification and differentiation decisions, little is know regarding the role of transcription factors in the specification and maintenance of maturation events. One candidate maturation effector is MIST1, a secretory cell-restricted transcription factor that has been implicated in controlling regulated exocytosis events in a number of cell types. Embryonic knock-out of MIST1 generates acinar cells that fail to establish an apical-basal organization, fail to properly localize zymogen granule and fail to communicate intra-cellularly, making the exocrine organ highly suceptible to pancreatic diseases.
Publication Title
Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
We sorted CD4 T cells from patients with metastatic melanoma at baseline and after three doses of ipilimumab. Overall design: We examined the differential expression of epigenetic enzymes
Publication Title
Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 4 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor alpha (ER) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 ChIP analysis followed by validation showed that HOXB7 physically interacts with ER, and that the HOXB7-ER complex enhances transcription of many ER target genes including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR-HER2 signaling, inhibits transcription of miRNA-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER-target genes and HER2. Repressing MYC using small molecule inhibitors reverses these events, and causes regression of breast cancer xenografts. The MYC-HOXB7-HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer.
Publication Title
HOXB7 Is an ERα Cofactor in the Activation of HER2 and Multiple ER Target Genes Leading to Endocrine Resistance.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
We analyzed via microarray gene expression profiles in de-identified, clinically annotated samples from Ficoll-purified peripheral blood samples from 10 acute myeloid leukemia (AML) patients in remission and 10 healthy donors collected under IRB-approved protocols.
Publication Title
Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy.
Sample Metadata Fields
Sex, Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 32 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells led to apoptosis and cell death in vitro and attenuated tumor growth in vivo in a xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further exploration of clinically used inhibitors of RNR as a therapeutic approach in treating this cancer.
Publication Title
Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Saccharomyces cerevisiae
- 6 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Experiments performed over the past three decades have shown that nucleosomes are transcriptional repressors. In Saccharomyces cerevisiae, depletion of histone H4 results in the genome-wide transcriptional de-repression of hundreds genes. The mechanism of de-repression is hypothesized to be rooted directly in chromatin changes. To test this, we reproduced classical H4 depletion experiments by conditional repression of all histone H3 transcription, which depletes the supply of nucleosomes in vivo. RNA-seq results were consistent with the earlier studies, but much more sensitive, revealing nearly 2500 de-repressed genes. Changes in chromatin organization were determined by MNase-seq. Nucleosomes that were preferentially retained occurred in regions of high DNA-encoded nucleosome affinity, and were marked with H3K36me2, which is linked to transcription elongation. Nucleosomes harboring acetyl marks or that contained the variant histone H2A.z were preferentially lost. Genes that were de-repressed lost or rearranged nucleosomes at their promoter, but not in the gene body. Therefore, a combination of DNA-encoded nucleosome stability and nucleosome composition dictates which nucleosomes will be lost under conditions of limiting histone protein. This, in turn, governs which genes will experience a loss of regulatory fidelity. Overall design: MNase-seq experiments consist of three wildtype (1 single-end and 2 paired-end) and four mutant (DCB200.1/H3 shutoff; 2 single-end, 2 paired-end) replicates. Each replicate contains two timepoints reflecting chromatin immediately after ("O hours") and 3 hours after transition to media containing dextrose. RNA-seq data includes three replicates from wildtype or H3 depleted cells after 3 hours in media containing dextrose.
Publication Title
In vivo effects of histone H3 depletion on nucleosome occupancy and position in Saccharomyces cerevisiae.
Sample Metadata Fields
Cell line, Subject, Time
View Samples