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SRP066150
Homo sapiens
9 Downloadable Samples
IlluminaGenomeAnalyzer
Description
Post-translational modifications, such as poly(ADP-ribosyl)ation (PARylation), regulate chromatin-modifying enzymes, ultimately affecting gene expression. This study explores the role of poly(ADP-ribose) polymerase (PARP) on global gene expression in a lymphoblastoid B cell line. We found that inhibition of PARP catalytic activity with olaparib resulted in global gene deregulation, affecting approximately 11% of genes expressed. Gene ontology analysis revealed that PARP could exert these effects through transcription factors and chromatin-remodeling enzymes, including the Polycomb Repressive Complex 2 (PRC2) member EZH2. EZH2 mediates the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification associated with chromatin compaction and gene silencing. Both pharmacological inhibition of PARP and knockdown of PARP1 induced the expression of EZH2 that resulted in increased global H3K27me3. Chromatin immunoprecipitation confirmed that PARP1 inhibition led to H3K27me3 deposition at EZH2-target genes, which resulted in gene silencing. Moreover, increased EZH2 expression is attributed to occupancy loss of the transcription repressor E2F4 at the EZH2 promoter following PARP inhibition. Together, these data show that PARP plays an important role in global gene regulation and identifies for the first time a direct role of PARP1 in regulating the expression and function of EZH2. Overall design: Examination of the effect of PARP inhibition on global gene expression in LCLs cell lines. mRNA profiles of LCLs cells lines treated at different time points with olaparib were generated by deep sequencing, in triplicate, using Illumina GAIIx.
Publication Title
Global Transcriptome Analysis Reveals That Poly(ADP-Ribose) Polymerase 1 Regulates Gene Expression through EZH2.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To identify gene(s) that are modified in their relative expression levels in the Potocki-Lupski Syndrome mouse model and map to the rearranged region, i.e. possible candidate genes at the source of the PTLS-like phenotypes shown by the PTLS mouse, we comp
Publication Title
Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki-Lupski syndrome.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 2 Downloadable Samples
- Illumina HiSeq 2000
Description
An increasingly common method for predicting gene activity is genome-wide chromatin immunoprecipitation of ‘active’ chromatin modifications followed by massively parallel sequencing (ChIP-seq). Using a novel ChIP-seq quantification method (cRPKM), we tested the power of such ChIP-seq strategies to predict relative protein and RNA levels at the pre-pro-B and pro-B differentiation stages in early B cell lymphopoiesis. Using a multi-omics approach that compares promoter chromatin status (ChIP-seq; published in GSE:21978) with ongoing active transcription (GRO-seq; published in GSE:40173), steady state mRNA (RNA-seq), inferred mRNA stability, and relative proteome abundance measurements (iTRAQ), we demonstrate that active chromatin modifications at promoters are a good indicator of transcription and steady state mRNA levels. Moreover, we found that promoters with active chromatin modifications exclusively in one of these cell states frequently predicted differentially expressed proteins. However, we found that many genes whose promoters have non-differential but active chromatin modifications also displayed changes in expression of their cognate proteins. This large class of developmentally and differentially regulated proteins that was uncoupled from chromatin status used mostly post-transcriptional mechanisms. Interestingly, the most differentially expressed protein in our B-cell development system, 2410004B18Rik, was regulated by a post-transcriptional mechanism, which further analyses indicated was mediated by an identified miRNA. These data provide a striking example of how our integrated multi-omics data set can be useful in uncovering regulatory mechanisms. Overall design: Total RNA from mouse pre-pro-B and pro-B cells, depleted of rRNA and small RNAs, was sequenced using a strand specific, single end sequencing strategy.
Publication Title
Prediction of Gene Activity in Early B Cell Development Based on an Integrative Multi-Omics Analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 61 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To study the effect of structural changes on expression, we assessed gene expression in genomic disorder mouse models. Both a microdeletion and its reciprocal microduplication mapping to mouse chromosome 11 (MMU11), which model the rearrangements present in Smith-Magenis (SMS) and Potocki-Lupski (PTLS) syndromes patients, respectively, have been engineered. We profiled the transcriptome of five different tissues affected in human patients in mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+) and uniallelic 2n (Deletion/Duplication) copies of the same region in an identical genetic background. The most differentially expressed transcripts between the four studied genotypes were ranked. A highly significant propensity, are mapping to the engineered SMS/PTLS interval in the different tissues. A statistically significant overrepresentation of the genes mapping to the flanks of the engineered interval was also found in the top-ranked differentially expressed genes. A phenomenon efficient across multiple cell lineages and that extends along the entire length of the chromosome, tens of megabases from the breakpoints. These long-range effects are unidirectional and uncoupled from the number of copies of the copy number variation (CNV) genes. Thus, our results suggest that the assortment of genes mapping to a chromosome is not random. They also indicate that a structural change at a given position of the human genome may cause the same perturbation in particular pathways regardless of gene dosage. An issue that should be considered in appreciating the contribution of this class of variation to phenotypic features.
Publication Title
Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
The nuclear hormone receptor, estrogen receptor-alpha (ER), and MAP kinases both play key roles in hormone-dependent cancers, yet their interplay and the integration of their signaling inputs remain poorly understood. In these studies, we document that estrogen-occupied ER activates and interacts with ERK2, a downstream effector in the MAPK pathway, resulting in ERK2 and ER colocalization at chromatin binding sites across the genome of breast cancer cells.
Publication Title
Genomic collaboration of estrogen receptor alpha and extracellular signal-regulated kinase 2 in regulating gene and proliferation programs.
Sample Metadata Fields
Disease, Disease stage, Cell line, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
ERRa and ERRg are essential transcriptional regulators of cardiac metabolism and functions. Here we extend our previous studies by analyzing the transcriptome changes in ERRa/ERRg KO hearts Overall design: RNA from 16-day-old mouse hearts were used. 2-3 mice per sample, 2 samples per genotype, 4 genotypes (aHetgWT, aHetgKO, aKOgWT, aKOgKO)
Publication Title
Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 3000
Description
Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 co-chaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells (ASCs). By analyzing Mzb1 -/- Prdm1 +/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of ASCs in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes. In addition, we find that Mzb1 -/- plasmablasts show a reduced activation of b1 integrin, which contributes to the impaired plasmablast differentiation and migration of ASCs to the bone marrow. Thus, Mzb1 function is required for multiple aspects of plasma cell differentiation. Overall design: Splenic B cells were purified from Mzb1 +/+ Prdm1 +/gfp and Mzb1 -/- Prdm1 +/gfp mice using anti-B220 magnetic beads and cultured in the presence of 25ug/ml LPS. After 4 days, undifferentiated CD138 - Blimp - B cell blasts (Activated B Cells), CD138 - Blimp + (Pre-PB cells), and CD138 + Blimp + (PB cells) were isolated with FACSAria (Becton Dickinson) sort.
Publication Title
Cochaperone Mzb1 is a key effector of Blimp1 in plasma cell differentiation and β1-integrin function.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Baseline gene expression for two primary and two recurrent tumor cell lines derived from MTB;TAN transgenic mice. Microarrays were performed in biological duplicate to determine differential gene expression between primary and recurrent tumor cell cohorts.
Publication Title
Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
E47 represses Foxp3 transcription, albeit indirectly through the activation of unknown negative regulatory of Foxp3 transcription.
Publication Title
Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell.
Publication Title
Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection.
Sample Metadata Fields
Specimen part
View Samples