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GSE11358
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Transcriptional dysregulation plays a major role in the pathology of Huntington's disease (HD). However, the mechanisms causing selective downregulation of genes remain unknown. Histones regulate chromatin structure and thereby control gene expression; recent studies have demonstrated a therapeutic role for histone deacetylase (HDAC) inhibitors in polyglutamine diseases. This study demonstrates that despite no change in overall acetylated histone levels, histone H3 is hypo-acetylated at promoters of downregulated genes in R6/2 mice, ST14a and STHdh cells, as demonstrated by in vivo chromatin immunoprecipitation. In addition, HDAC inhibitor treatment increases association of acetylated histones with downregulated genes and corrects mRNA abnormalities. In contrast, there is a decrease in mRNA levels in wild-type cells following treatment with a histone acetyltransferase inhibitor. Although changes in histone acetylation correlate with decreased gene expression, histone hypo-acetylation may be a late event, as no hypo-acetylation is observed in 4-week-old R6/2 mice. Nevertheless, treatment with HDAC inhibitors corrects mRNA abnormalities through modification of histone proteins and may prove to be of therapeutic value in HD.
Publication Title
Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
Illumina Genome Analyzer IIx, Illumina HiSeq 2000
Description
Transcriptional dysregulation is an early feature of Huntington''s disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin (Htt) expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. Overall design: mRNA-seq in wild type and R6/2 cortex and striatum at 8 and 12 weeks.
Publication Title
Targeting H3K4 trimethylation in Huntington disease.
Sample Metadata Fields
Age, Specimen part, Subject
View Samples- Mus musculus
- 25 Downloadable Samples
- Illumina HiSeq 2500
Description
Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of PRC2 and used the resultant data to screen for novel potential targets. The RNA polymerase II (Pol II) transcription factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of many, but not all, PRC2 target genes as measured by both steady state and nascent RNA levels. We propose that PRC2 regulates transcription of a subset of target genes in part via methylation of EloA. Overall design: We examined the transcripitonal profile of EEDnull, EloAnull, EloA mutant, and parental mouse embryonic stem cells by RNAseq. Please note that the .bw processed data file was generated from the *mESC replicate samples together and linked to the corresponding *rep1 sample records.
Publication Title
Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2500
Description
Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of PRC2 and used the resultant data to screen for novel potential targets. The RNA polymerase II (Pol II) transcription factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of many, but not all, PRC2 target genes as measured by both steady state and nascent RNA levels. We propose that PRC2 regulates transcription of a subset of target genes in part via methylation of EloA. Overall design: We examined the nascent transcripiton profile of mES cells by adding 5-Bromouridine (BrU) to the media for 10 min. Following RNA isolation, BrU-labelled nascent RNA species were affinity purified using BrdU antibody and sequenced after library preparation. Please note that each .bw file was generated from two replicate samples together and linked to the corresponding *rep1 sample records.
Publication Title
Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription.
Sample Metadata Fields
Specimen part, Subject
View Samples- Danio rerio
- 20 Downloadable Samples
- IlluminaHiSeq2000
Description
Subclassification of lymphoid neoplasms is often based on the presumed cell of origin based on T and B progenitor gene expression and the effect of cell lineage on influencing functional characteristics such as aggression and self-renewal capacity is largely unknown, accounted for in part, by lack of experimental models to address these questions. Here, we have used transgenic zebrafish to create the first models of Myc-induced B-ALL and mixed phenotypic B/T-ALL, opening new avenues for studying the these leukemias in the zebrafish. Our work has utilized syngeneic strain zebrafish, limiting dilution cell transplantation, and the widely reported rag2-Myc transgenic model to provide new understanding of how strain differences can underlie leukemia onset in the zebrafish model. Even more importantly, our work now for the first time, has allowed assessment of cell lineage on dictating aggression and leukemia stem cell frequency independent of the underlying oncogenic driver. In total, our work uncoveres that T-ALLs are more aggressive and have higher numbers of leukemia stem cells when compared with B-ALL and mixed phenotypic ALL. Furthermore, analysis of our biphenotypic B/T-ALL suggests that B cell pathways lock cells in less aggressive and lower stem cell fates and are dominant in regulating these processes when T cell pathways are co-regulated within ALL cells. Overall design: The goal of our study is to determine the transcriptional profiles of high and low self-renewing capacity tumors. 20 samples total: 11 unique samples (9 samples with biological replicates), 6 high self-renewing tumors (>1% cells could initiate leukemia) and 5 low self-renewing tumors (<1% of cells could initiate leukemia).
Publication Title
Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
X-chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X-chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSC) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X-reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X-chromosome to cancer in mice. Thus, Xist RNA is not only required to maintain XCI but also suppresses cancer in vivo.
Publication Title
Xist RNA is a potent suppressor of hematologic cancer in mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 1000
Description
Purpose: determine RNA expression differences in an unbiased fashion between UPS tumors derived from LSL-KrasG12D;Trp53-/- (KP) mice, and UPS tumors derived from LSL-KrasG12D;Trp53-/-;Epas1-/- (KPH2) mice. Epas1 encodes HIF-2alpha protein. Overall design: RNA-seq was performed on KP (n = 4) and KPH2 (n = 4) derived UPS tumors using Illumina HiSeq 2000.
Publication Title
Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Master regulatory genes require stable silencing by the Polycomb-Group (PcG) to prevent improper expression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in mouse ES cells and neural progenitors using high-resolution 5C technology and super-resolution microscopy. The genomic loci of repressed PcG target genes formed discrete, small domains of tight interaction that corresponded to locations bound by canonical Polycomb Repressive Complex 1 (PRC1). These domains changed during differentiation as PRC1 binding changed. Their formation depended upon the Polyhomeotic component of canonical PRC1, and occurred independently of PRC1-catalyzed ubiquitylation. PRC1 domains differ from topologically associating domains in numerous aspects . These domains have the potential to play a key role in transmitting epigenetic silencing of PcG targets by linking PRC1 to formation of a repressive higher order structure. Overall design: RNA-Seq was performed to compare gene expression of in vitro derived NPC and Phc1 knock-out mESC with wild type ESC. Experiments were performed in dupicates. 50base single end sequencing was performed on Illumina HiSeq2000. Reference genome is mm9.
Publication Title
Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Caenorhabditis elegans
- 9 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
Many pathogens secrete toxins that target key host processes resulting in the activation of immune pathways. The secreted Pseudomonas aeruginosa toxin Exotoxin A (ToxA) disrupts intestinal protein synthesis which triggers the induction of a subset of P. aeruginosa-response genes in the nematode Caenorhabditis elegans. We found that losing one ToxA-induced C. elegans gene, the Tribbles pseudokinase ortholog nipi-3, results in hypersusceptibility to both P. aeruginosa and ToxA. We determined that NIPI-3 mediates the post-developmental expression of intestinal immune genes and proteins and primarily functions in parallel to known immune pathways, including p38 PMK-1 MAPK signaling. Here we present the microarray data that was used to determine that (1) nipi-3 regulates immune gene expression and that (2) nipi-3 and pmk-1 regulate non-overlapping gene sets consistent with them functioning in parallel.
Publication Title
Tribbles ortholog NIPI-3 and bZIP transcription factor CEBP-1 regulate a Caenorhabditis elegans intestinal immune surveillance pathway.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Celiac disease (CeD) is an intestinal immune-mediated disorder caused by gluten ingestion in genetically predisposed subjects. CeD is characterized by villous atrophy, altered intestinal permeability, crypt hyperplasia and innate and adaptive immune response. This study aimed to develop and validate the use of intestinal organoids from celiac patients to study CeD. A repository of organoids from duodenum of non-celiac and celiac patients was generated and characterized accordingly to standard procedures. RNA-seq analysis was employed to study the global gene expression program of CeD (n=3) and non-CeD (n=3) organoids sets. While the three celiac derived organoids shared similar transcriptional signatures the NC samples set appeared more heterogeneous. We found 486 genes differentially expressed between the two groups. Of them, 299 genes were downregulated (FC<2; FDR<0.05) and 187 were upregulated in CeD (FC >2; FDR<0.05). We observed CeD organoids had significantly altered expression of genes associated with barrier function, innate immunity, and stem cell function. Overall design: mRNA profiles of 3 non-celiac healthy controls and 3 celiac organoids derived from duodenal biopsies.
Publication Title
Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease.
Sample Metadata Fields
Specimen part, Disease, Subject
View Samples