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GSE73771
Mus musculus
10 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PCR2 writing of H3K27me3 is mechanistically required for gene silencing. Here we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (Embryonic Ectoderm Development) inactivation in the postnatal heart (Eed CKO ) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in Eed CKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized Eed CKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.
Publication Title
EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
Illumina HiSeq 2500
Description
Through H3K27me3 and H3K27ac ChIP-seq and RNA-seq data in wile-tpye (WT) and EED-knockout (CKO) mouse cardiomyocytes, we unexpectedly uncovered a novel mechanism of PRC2-mediated gene repression. EED inactivation in the postnatal heart (EEDCKO) caused progressive, lethal dilated cardiomyopathy, with upregulation of components of the slow-twitch muscle gene program. Surprisingly, upregulation of these genes was not associated with their loss of H3K27me3, but rather with their gain of H3K27 acetylation (H3K27ac), an activating histone mark. Moreover, re-expression of EED in juvenile hearts rescued heart function and normalized H3K27ac, but not H3K27me3. Overall design: RNA-seq in isolated adult cardiomyocytes from 2-month old mice, Wildtype (WT or Het), cardiac conditional EED Knockout (CKO) and CKO injected with AAV9 expressing luciferase, EED or HDAC1/2..
Publication Title
EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2500
Description
Through H3K27me3 and H3K27ac ChIP-seq and microarray data in wile-tpye (WT) and EED-knockout (CKO) mouse cardiomyocytes, we unexpectedly uncovered a novel mechanism of PRC2-mediated gene repression. EED inactivation in the postnatal heart (EEDCKO) caused progressive, lethal dilated cardiomyopathy, with upregulation of components of the slow-twitch muscle gene program. Surprisingly, upregulation of these genes was not associated with their loss of H3K27me3, but rather with their gain of H3K27 acetylation (H3K27ac), an activating histone mark. Moreover, re-expression of EED in juvenile hearts rescued heart function and normalized H3K27ac, but not H3K27me3. Overall design: RNA-seq in isolated adult cardiomyocytes from 2-month old mice, Wildtype (WT) cardiac conditional EED Knockout (CKO).
Publication Title
EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Cyclin D1 is an important cell cycle regulator but in cancer its overexpression also increases cellular migration mediated by p27KIP1 stabilization and RhoA inhibition. Recently, a common polymorphism at the exon 4-intron 4 boundary of the human cyclin D1 gene within a splice donor region was associated with an altered risk of developing cancer. Altered RNA splicing caused by this polymorphism gives rise to a variant cyclin D1 isoform termed cyclin D1b, which has the same N-terminus as the canonical cyclin D1a isoform but a distinct C-terminus. Analysis was performed of mouse cyclin D1 knockout 3T3 cells infected with splice variants of cyclin D1. 3T3 cells transduced with retroviral vectors expressing each cyclin D1 isoform were processed for expression analysis.
Publication Title
Alternate cyclin D1 mRNA splicing modulates p27KIP1 binding and cell migration.
Sample Metadata Fields
No sample metadata fields
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
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
In order to identify transcript changes in response to DEF , we used human macrophages with or without DEF treatment. In order to study the effect of iron chelation on LPS-polarized macrophage transcriptome, we exposed DEF-treated or control macrophages to short time exposure to LPS. We then performed whole-genome transcriptome sequencing by RNA-sequencing (RNA-seq). Overall design: Macrophages from 3 healthy donors were either treated with DEF (500 µM - designated as DEF) or left unstimulated (CONTROL). LPS treatment (100 ng/ml, 3 hours) was performed in cells with DEF (designated as LPS+DEF) or without (LPS). RNA-seq was performed on Illumina Hiseq 2500
Publication Title
Acute Iron Deprivation Reprograms Human Macrophage Metabolism and Reduces Inflammation In Vivo.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina MouseRef-8 v2.0 expression beadchip
Description
DNA methylation and the Polycomb Repression System are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear. By genome-wide mapping of the Polycomb Repressive Complex 2 (PRC2)-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and PRC2 from Polycomb-target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression. An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining PRC2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease.
Publication Title
Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
RhoB null mice show decreases in pathological angiogenesis in the ischemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge.
Publication Title
RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 20 Downloadable Samples
- Illumina HiSeq 2000
Description
This dataset is part of a study that investigated how the hematopoietic system coordinates the rapid and efficient regeneration of the megakaryocytic lineage during stress scenarios. We found that the phenotypic hematopoietic stem cell (HSC) compartment contains stem-like megakaryocyte-committed progenitors (SL-MkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. This dataset contains single-cell RNA sequencing data of 30 hematopoietic stem and progenitor cells which, in the context of our study, confirmed that MK-specfic transcripts are of highly variable expression in HSCs. The dataset further showed that variations in MK transcript expression in HSCs is not correlated with global transcriptomic rearrangements. Overall design: Murine bone marrow cells were sorted by Lin-cKit+CD150+CD48- (referred to as cd150+ in the following) and Lin-cKit+CD150- (referred to as cd150- in the following). Transcriptomes of 11 cd150- and 9 cd150+ HSCs were determined using QUARTZ, a single-cell RNASeq protocol
Publication Title
Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors.
Sample Metadata Fields
No sample metadata fields
View Samples