Histone modifications are a key epigenetic mechanism to activate or repress the expression of genes. Data sets of matched microarray expression data and histone modification data measured by ChIP-seq exist, but methods for integrative analysis of both data types are still rare. Here, we present a novel bioinformatic approach to detect genes that are differentially expressed between two conditions putatively caused by alterations in histone modification. We introduce a correlation measure for integrative analysis of ChIP-seq and gene expression data and demonstrate that a proper normalization of the ChIP-seq data is crucial. We suggest applying Bayesian mixture models of different distributions to further study the distribution of the correlation measure. The implicit classification of the mixture models is used to detect genes with differences between two conditions in both gene expression and histone modification. The method is applied to different data sets and its superiority to a naive separate analysis of both data types is demonstrated. This GEO series contains the expression data of the Cebpa example data set.
Integrative analysis of histone ChIP-seq and transcription data using Bayesian mixture models.
No sample metadata fields
View SamplesTranslocations involving the MLL genes are frequently found in Acute Myeloid Leukemia (AML) and are associated with poor prognosis. The MLL fusion proteins act as aberrant transcription factor activating a transcriptional program that transforms the cells, potentially through collaboration with other transcription factors. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBP to be up-regulated in the AML samples, suggesting that C/EBP might collaborate with MLL fusion proteins in the initial transformation process. We could show that transformation by MLL fusion proteins is dependent on C/EBP activity both in early progenitors as well as in GMPs. In contrast, C/EBP was found to be indispensable in an already established leukemia. These results suggest that C/EBP play an important role in the early transforming event of leukemogenesis.
Initiation of MLL-rearranged AML is dependent on C/EBPα.
Specimen part
View SamplesIn this study, we use a conditional mouse model for Cebpa to investigate the significance of C/EBP in HSCs. The frequency of HSCs is unaltered following deletion of C/EBP, however, upon serial transplantations of either full BM or purified HSCs, the stem cells and stem cell activity is lost. This is not due to increased proliferation, but rather caused by a shift from quiescence to apoptosis with a resultant exhaustion of the stem cell pool. We identify direct C/EBP target genes by combining genome-wide C/EBP ChIP-seq analysis in stem and progenitor cells with gene expression data from HSC with and without C/EBP. Furthermore, we explore the impact of C/EBP on active and repressive histone modifications by doing functional genome-wide ChIP-seq analysis of H3K4Me3 and H3K27Me3 in stem and progenitor cells with and without C/EBP.
C/EBPα is required for long-term self-renewal and lineage priming of hematopoietic stem cells and for the maintenance of epigenetic configurations in multipotent progenitors.
Sex, Specimen part
View SamplesTo investigate the role of the transcription factor ERG in hematopoiesis we generated Erg heterozygous knockout and conditional Erg knockout mice. We found that several hematopoietic cell types were decreased in these mice. To define Erg downstream target genes in hematopoietic stem cells, we sorted Lineage-, Sca-1+, c-kit+, CD150+, CD48- cells from Erg +/- mice for gene expression analysis. To define Erg downstream target genes in hematopoietic progenitors, we sorted multipotent progenitors (Lineage-, Sca-1+, c-kit+, CD150-) from Erg -/- mice for gene expression analysis.
ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.
Sex, Specimen part
View SamplesIn tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing the surrounding vasculature network. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines responded strikingly different to hypoxia. We demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response. Overall design: 16 paired-end samples in total: 4 different cell lines sequenced in duplicate across 2 conditions each.
Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia.
Specimen part, Treatment, Subject
View SamplesMalignant mesothelioma (MM) is an asbestos-related malignancy and largely unresponsive to conventional chemotherapy or radiotherapy. Novel, more effective therapeutic strategies are needed for this fatal disease. We performed microarray analysis of MM using Affymetrix Human U133 Plus 2.0 array. Aberrant expression of the genes participating in semaphorin signaling were detected in malignant mesothelioma cells. All MM cells downregulated the expression of more than one gene for SEMA3B, 3F, and 3G when compared with Met5a, a normal pleura-derived cell line. In 12 of 14 epithelioid MM cells, the expression level of SEMA3A was lower than that in Met5a. An augmented expression of VEGFA was detected in half of the MM cells. The expression ratio of VEGFA/SEMA3A was significantly higher in the epithelioid MMs than in Met5a and the non-epithelioid MMs. Next, gene expression profiling for the polycomb and trithorax group genes revealed that expression of BAP1, the catalytic subunit of the polycomb repressive deubiquitinase complex, and many trithorax group genes was downregulated in MMs compared with the expression of the same genes in Met5a cells. Perturbation of the polycombtrithorax balance plays a significant role in the pathogenesis of malignant mesothelioma.
Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells.
Sex, Age, Specimen part, Cell line
View SamplesGametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells. Overall design: RNA-seq and ChIP-seq analyses using wild-type and Scml2-KO spermatogenic cells
Poised chromatin and bivalent domains facilitate the mitosis-to-meiosis transition in the male germline.
No sample metadata fields
View SamplesGene expression data from mouse organs after Advax injection
Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines.
Sex, Specimen part
View SamplesTranscriptional profiling of oral keratinocytes was utilized to define the biological role of P. gingivalis SerB.
Role of Porphyromonas gingivalis SerB in gingival epithelial cell cytoskeletal remodeling and cytokine production.
No sample metadata fields
View SamplesA minor population of M cells within the follicle-associated epithelium (FAE) of intestinal Peyers patches (PP) serves as a major portal for entry of exogenous antigens. Characterization of the mammalian M cells, including identification of M-cell surface molecules used for bacterial uptake, has been hampered by their relative rarity. In contrast, M cells constitute virtually all of the FAE cells in the avian bursa of Fabricius. We therefore performed comparative gene expression profiling of chicken and murine FAE to identify commonly expressed genes by M cells in both species. The comprehensive transcriptome analysis revealed that 28 genes were commonly up-regulated in FAE from both species. In situ hybridization (ISH) revealed that annexin A10 (Anxa10) mRNA was scattered in FAE, and co-localized with Ulex europaeus agglutinin-1(UEA-1) that binds to M cells. Whole-mount immunostaining also revealed that cellular prion protein (PrPC) was expressed on the luminal side of the apical plasma membrane of M cells, and co-localized with grycoprotein2 (GP2) that recognizes only M cells in murine PP. Taken together, we found new M-cell-specific molecules by using comprehensive transcriptome analysis. These molecules conserved in M cells from both species might play critical roles in M-cell function and/or differentiation.
New approach for m-cell-specific molecules screening by comprehensive transcriptome analysis.
Age, Specimen part, Disease, Disease stage
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