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GSE31123
Mus musculus
4 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Metastasis to lymph nodes is an early and prognostically important event in the progression of many human cancers, and is associated with expression of vascular endothelial growth factor-D (VEGF-D). Changes to lymph node vasculature occur during metastasis, and may establish a metastatic niche capable of attracting and supporting tumor cells.
Publication Title
A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 36 Downloadable Samples
NextSeq 500
Description
Understanding the specific cell populations responsible for propagation of leukemia is an important step for development of effective targeted therapies. Recently, the lymphoid-primed multipotent progenitor (LMPP) has been proposed to be a key propagating population in acute myeloid leukemia (AML; PMID 21251617). We have also shown that LMPPs share many functional and gene expression properties with early thymic progenitors (ETPs; PMID 22344248). This finding is of particular interest as ETP leukemias have recently been described: a distinct and poor prognostic disease entity with a transcriptional profile reminiscent of murine ETPs, showing co-expression of hematopoietic stem cell (HSC) and myeloid markers (PMID 19147408). Together, this raises the question whether ETPs can act as a leukemia-initiating/propagating cell population; however, relevant disease models to test this hypothesis are currently lacking. Analysis of the genetic landscape of ETP leukemias has revealed frequent coexistence of inactivating mutations of EZH2 and RUNX1 (PMID 22237106). We therefore generated mice with deletions of Ezh2 and Runx1 specifically targeted to early lymphoid progenitors using Rag1Cre (Ezh2fl/flRunx1fl/flRag1Cre+; DKO mice). As anticipated, HSCs lacked significant recombination in DKO mice whereas close to 100% of purified ETPs (Lin-CD4-CD8-CD44+CD25-Kit+Flt3+) showed deletion of Ezh2 and Runx1. Strikingly, despite a 16-fold reduction in thymus cellularity caused by a block in thymocyte maturation at the DN2-DN3 transition, absolute numbers of ETPs within the thymus of DKO mice were markedly expanded (12-fold; p<0.0001). In contrast, Ezh2 or Runx1 deletion alone had no impact on numbers of ETPs. RNA-sequencing of the expanded ETPs in DKO mice revealed upregulation of HSC- and myeloid-associated transcriptional programs, reminiscent of ETP leukaemia e.g. Pbx1 (log2FC=3.0; p<0.0001) and Csf3r (log2FC=1.9; p=0.0038). Single-cell gene expression analysis confirmed co-expression of HSC and myeloid programs with lymphoid genes within individual DKO ETPs. Further, some key regulators of T-cell maturation which are aberrantly expressed in ETP leukemia were also disrupted in DKO ETPs e.g. Tcf7 (log2FC=-9.5; p<0.0001). Gene expression associated with aberrant Ras signalling was also present. However, despite a continued expansion of the ETP population with age, we did not observe leukemia in DKO mice with over 1 year of follow-up. Since ETP leukemias frequently feature activating mutations in genes regulating RAS signaling, we hypothesised that the expanded “pre-leukemic” ETPs in DKO mice would be primed for leukemic transformation by signalling pathway mutation. We therefore crossed DKO mice with a Flt3ITD/+ knock-in mouse line, as internal tandem duplications (ITD) of FLT3 are frequent in ETP leukemias. Ezh2fl/flRunx1fl/flRag1Cre+Flt3ITD/+ (DKOITD) mice showed dramatically reduced survival (median 9.3 weeks) resulting from an aggressive, fully penetrant acute leukemia showing a predominantly myeloid phenotype (e.g. Mac1) but with co-expression of some lymphoid antigens (e.g. intracellular CD3). Crucially, this leukaemia could be propagated in wild-type recipients upon transplantation of the expanded ETPs. DKOITD ETPs were transcriptionally very similar to DKO ETPs, retaining expression of lymphoid alongside HSC- and myeloid-associated genes. Finally, in a lympho-myeloid cell line model (EML cells) we demonstrated that Ezh2 inactivation-induced loss of H3K27me3 is associated with a corresponding increase in H3K27Ac, a transcriptional activating signal that recruits bromodomain proteins. As such, we reasoned that our ETP leukemia model might be sensitive to bromodomain inhibitors such as JQ1. Indeed, we observed high sensitivity of expanded DKOITD ETPs to JQ1, raising the possibility of a new therapeutic approach for ETP leukemias. This novel mouse model of ETP-propagated leukemia, driven by clinically relevant mutations, provides intriguing evidence that leukemias with a predominant myeloid phenotype, but co-expressing lymphoid genes, may initiate within a bona fide early lymphoid progenitor population. Since the functional characteristics of the cell of origin of a leukaemia may direct its progression and response to therapy, these findings could have important implications for future stratification and treatment of both AML and ETP leukemias. Overall design: mRNA-sequencing of mouse Mac1+ bone marrow cells from three genotypes
Publication Title
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
Understanding the specific cell populations responsible for propagation of leukemia is an important step for development of effective targeted therapies. Recently, the lymphoid-primed multipotent progenitor (LMPP) has been proposed to be a key propagating population in acute myeloid leukemia (AML; PMID 21251617). We have also shown that LMPPs share many functional and gene expression properties with early thymic progenitors (ETPs; PMID 22344248). This finding is of particular interest as ETP leukemias have recently been described: a distinct and poor prognostic disease entity with a transcriptional profile reminiscent of murine ETPs, showing co-expression of hematopoietic stem cell (HSC) and myeloid markers (PMID 19147408). Together, this raises the question whether ETPs can act as a leukemia-initiating/propagating cell population; however, relevant disease models to test this hypothesis are currently lacking. Analysis of the genetic landscape of ETP leukemias has revealed frequent coexistence of inactivating mutations of EZH2 and RUNX1 (PMID 22237106). We therefore generated mice with deletions of Ezh2 and Runx1 specifically targeted to early lymphoid progenitors using Rag1Cre (Ezh2fl/flRunx1fl/flRag1Cre+; DKO mice). As anticipated, HSCs lacked significant recombination in DKO mice whereas close to 100% of purified ETPs (Lin-CD4-CD8-CD44+CD25-Kit+Flt3+) showed deletion of Ezh2 and Runx1. Strikingly, despite a 16-fold reduction in thymus cellularity caused by a block in thymocyte maturation at the DN2-DN3 transition, absolute numbers of ETPs within the thymus of DKO mice were markedly expanded (12-fold; p<0.0001). In contrast, Ezh2 or Runx1 deletion alone had no impact on numbers of ETPs. RNA-sequencing of the expanded ETPs in DKO mice revealed upregulation of HSC- and myeloid-associated transcriptional programs, reminiscent of ETP leukaemia e.g. Pbx1 (log2FC=3.0; p<0.0001) and Csf3r (log2FC=1.9; p=0.0038). Single-cell gene expression analysis confirmed co-expression of HSC and myeloid programs with lymphoid genes within individual DKO ETPs. Further, some key regulators of T-cell maturation which are aberrantly expressed in ETP leukemia were also disrupted in DKO ETPs e.g. Tcf7 (log2FC=-9.5; p<0.0001). Gene expression associated with aberrant Ras signalling was also present. However, despite a continued expansion of the ETP population with age, we did not observe leukemia in DKO mice with over 1 year of follow-up. Since ETP leukemias frequently feature activating mutations in genes regulating RAS signaling, we hypothesised that the expanded “pre-leukemic” ETPs in DKO mice would be primed for leukemic transformation by signalling pathway mutation. We therefore crossed DKO mice with a Flt3ITD/+ knock-in mouse line, as internal tandem duplications (ITD) of FLT3 are frequent in ETP leukemias. Ezh2fl/flRunx1fl/flRag1Cre+Flt3ITD/+ (DKOITD) mice showed dramatically reduced survival (median 9.3 weeks) resulting from an aggressive, fully penetrant acute leukemia showing a predominantly myeloid phenotype (e.g. Mac1) but with co-expression of some lymphoid antigens (e.g. intracellular CD3). Crucially, this leukaemia could be propagated in wild-type recipients upon transplantation of the expanded ETPs. DKOITD ETPs were transcriptionally very similar to DKO ETPs, retaining expression of lymphoid alongside HSC- and myeloid-associated genes. Finally, in a lympho-myeloid cell line model (EML cells) we demonstrated that Ezh2 inactivation-induced loss of H3K27me3 is associated with a corresponding increase in H3K27Ac, a transcriptional activating signal that recruits bromodomain proteins. As such, we reasoned that our ETP leukemia model might be sensitive to bromodomain inhibitors such as JQ1. Indeed, we observed high sensitivity of expanded DKOITD ETPs to JQ1, raising the possibility of a new therapeutic approach for ETP leukemias. This novel mouse model of ETP-propagated leukemia, driven by clinically relevant mutations, provides intriguing evidence that leukemias with a predominant myeloid phenotype, but co-expressing lymphoid genes, may initiate within a bona fide early lymphoid progenitor population. Since the functional characteristics of the cell of origin of a leukaemia may direct its progression and response to therapy, these findings could have important implications for future stratification and treatment of both AML and ETP leukemias. Overall design: mRNA-sequencing of mouse early thymic precursors from three genotypes
Publication Title
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. Overall design: RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.
Publication Title
Dach2-Hdac9 signaling regulates reinnervation of muscle endplates.
Sample Metadata Fields
No sample metadata fields
View Samples- Saccharomyces cerevisiae
- 24 Downloadable Samples
- Affymetrix Yeast Genome S98 Array (ygs98)
Description
Duplicated genes escape gene loss by conferring a dosage benefit or evolving diverged functions. The yeast Saccharomyces cerevisiae contains many duplicated genes encoding ribosomal proteins. Prior studies have suggested that these duplicated proteins are functionally redundant and affect cellular processes in proportion to their expression. In contrast, through studies of ASH1 mRNA in yeast, we demonstrate paralog-specific requirements for the translation of localized mRNAs. Intriguingly, these paralog-specific effects are limited to a distinct subset of duplicated ribosomal proteins. Moreover, transcriptional and phenotypic profiling of cells lacking specific ribosomal proteins reveals differences between the functional roles of ribosomal protein paralogs that extend beyond effects on mRNA localization. Finally, we show that ribosomal protein paralogs exhibit differential requirements for assembly and localization. Together, our data indicate complex specialization of ribosomal proteins for specific cellular processes, and support the existence of a ribosomal code.
Publication Title
Functional specificity among ribosomal proteins regulates gene expression.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2 Downloadable Samples
- IlluminaHiSeq2000
Description
To understand the funtion of Colorectal cancer GWAS results, we perform a comprehensive analysis using biofeatures of HCT116 colon cancer cell line and got a list of risk-asscociated SNP. Risk-associated SNP are likely exerting their effects through promoters or enhancer. In order to understand the importance of the genes with risk-associated SNP in their promoters and enhancers'' putatively targeted genes, we did a comparison of these genes between HCT116 colon cancer cell and normal colon and try to understand their function Overall design: Two biological replicates of HCT116 were compared to the data of two normal colon samples already deposited in GEO (GSM1010974 and GSM1010942).
Publication Title
Functional annotation of colon cancer risk SNPs.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
While transcriptional regulation of stem cell self-renewal and differentiation has been extensively studied, only a small number of studies have addressed the roles for post-translational modifications in these processes. A key mechanism of post-translational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Using UPS-targeted RNAi screens, we identify novel regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme, Psmd14, and the E3 ligase, Fbxw7, and characterize their importance in ES cell pluripotency and cellular reprogramming.
Publication Title
Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
While transcriptional regulation of stem cell self-renewal and differentiation has been extensively studied, only a small number of studies have addressed the roles for post-translational modifications in these processes. A key mechanism of post-translational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Using UPS-targeted RNAi screens, we identify novel regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme, Psmd14, and the E3 ligase, Fbxw7, and characterize their importance in ES cell pluripotency and cellular reprogramming.
Publication Title
Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HiSeq 2000
Description
We have analyzed publicly available K562 Hi-C data, which enables genome-wide unbiased capturing of chromatin interactions, using a Mixture Poisson Regression Model to define a highly specific set of interacting genomic regions. We integrated multiple ENCODE Consortium resources with the Hi-C data, using DNase-seq data and ChIP-seq data for 46 transcription factors and 8 histone modifications. We classified 12 different sets (clusters) of interacting loci that can be distinguished by their chromatin modifications and which can be categorized into three types of chromatin hubs. The different clusters of loci display very different relationships with transcription factor binding sites. As expected, many of the transcription factors show binding patterns specific to clusters composed of interacting loci that encompass promoters or enhancers. However, cluster 6, which is distinguished by marks of open chromatin but not by marks of active enhancers or promoters, was not bound by most transcription factors but was highly enriched for 3 transcription factors (GATA1, GATA2, and c-Jun) and 3 chromatin modifiers (BRG1, INI1, and SIRT6). To validate the identification of the clusters and to dissect the impact of chromatin organization on gene regulation, we performed RNA-seq analyses before and after knockdown of GATA1 or GATA2. We found that knockdown of the GATA factors greatly alters the expression of genes within cluster 6. Our work, in combination with previous studies linking regulation by GATA factors with c-Jun and BRG1, provide genome-wide evidence that Hi-C data identifies sets of biologically relevant interacting loci. Overall design: RNA-seq of control, siGATA1 and siGATA2 K562 cells
Publication Title
Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages.
Sample Metadata Fields
Cell line, Subject
View Samples