Yin Yang 1 (YY1) is a critical transcription factor controlling cell proliferation, development and DNA damage responses. Although two homologous Drosophila YY family members (pleiohomeotic (pho)) and pleiohomeotic-like (phol)) are redundant, the functional significance of a recently described mammalian YY1-like gene (YY2) is unknown. Using microarray and gene set enrichment analysis (GSEA), we found that lentiviral constructs containing short hairpin loop YY1- and YY2-specific inhibitory RNAs (shYY1 and shYY2) caused significant changes in both redundant and distinguishable expression patterns. Ribosomal protein genes were the most significant gene set up-regulated by both shYY1 and shYY2, although combined shYY1/shYY2 knockdowns were not additive. In contrast, shYY2 reversed anti-proliferative effects of shYY1 on E2F target genes, and shYY2 particularly altered UV damage response, platelet-specific genes and mitochondrial function genes. The most YY2-specific gene was the platelet glycoprotein CD36 whose ligand is thrombospondin - a key UV response gene. We found that decreases in YY1 or YY2 caused inverse changes in UV sensitivity, and that their combined loss reversed their respective individual effects. Taken together, our studies show that YY2 is not redundant to YY1, and YY2 is a significant regulator of genes previously thought to uniquely respond to YY1. Functions of thrombospondin and CD36 in inflammation, atherogenesis, innate immunity and malaria pathogenesis reveal new potential regulatory roles for YY1 and YY2.
Genome-wide analysis of YY2 versus YY1 target genes.
Cell line
View SamplesTranscriptome analysis of MCF-7 cells exposed for 48 hours to various concentrations of xenoestrogen chemicals.
Expressomal approach for comprehensive analysis and visualization of ligand sensitivities of xenoestrogen responsive genes.
Cell line
View SamplesTo examine whether the BPA-induced morphological alterations of the fetal mouse mammary glands are a) associated with changes in mRNA expression reflecting estrogenic actions and/or b) dependent on the estrogen receptor (ER), we compared the transcriptomal effects of BPA and the steroidal estrogen ethinylestradiol (EE2) on fetal mammary tissues of wild type and ER knock-out mice.
Low-dose BPA exposure alters the mesenchymal and epithelial transcriptomes of the mouse fetal mammary gland.
Sex, Specimen part
View SamplesTranscriptomes of mouse E12.5 primordial germ cells (PGCs), primordial germ cell-like cells (PGCLCs) isolated from 6-day culture embryoid bodies, and the precursor pluripotent stem cells [embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)] and epiblast-like cells (EpiLCs)
Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells.
Sex, Specimen part
View SamplesMCF7 cells were exposed to xenoestrogens (vehicle = 0.1% ethanol, 30 pM 17beta-estradiol, 3 micromolar genistein, 10 micromolar genistein, 1 micomolar daidzein, 10 nM bisphenol A, 10 nM para-nonylphenol, 3 nM PPT) for 48 hours.
No associated publication
No sample metadata fields
View SamplesInduced pluripotent stem (iPS) cells have been derived from various somatic cell populations through ectopic expression of defined factors. It remains unclear whether iPS cells generated from different cell types are molecularly and functionally similar. Here, we show that iPS cells obtained from fibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns. Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPS cells into embryoid bodies and different hematopoietic cells. Our results suggest that low-passage iPS cells retain a transient epigenetic memory of their somatic cells of origin, which manifests as differential gene expression and altered differentiation capacity. These observations might affect ongoing attempts to use iPS cells for disease modeling and also could be exploited for potential therapeutic applications to enhance differentiation into desired cell lineages.
Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.
Specimen part
View SamplesDevelopmental exposure of mouse fetuses to estrogens results in dose-dependent permanent effects on prostate morphology and function. Fetal prostatic mesenchyme cells express estrogen receptor alpha (ER) and androgen receptors and convert stimuli from estrogens and androgens into signaling to regulate epithelial cell proliferation and differentiation. To obtain mechanistic insight into the role of different doses of estradiol (E2) in regulating mesenchymal cells, we examined E2-induced transcriptomal changes in primary cultures of fetal mouse prostate mesenchymal cells. Urogenital sinus mesenchyme cells were obtained from male mouse fetuses at gestation day 17 and exposed to 10 pM, 100 pM or 100 nM E2 in the presence of a physiological concentration of dihydrotestosterone (0.69 nM) for four days. Gene ontology studies suggested that low doses of E2 (10 pM and 100 pM) induce genes involved in cell adhesion, morphological tissue development, and sterol biosynthesis but suppress genes involved in growth factor signaling and cell adhesion. Genes showing inverted-U-shape dose responses (enhanced by E2 at 10 pM E2 but suppressed at 100 pM) were identified, and their enrichment in the glycolytic pathway was demonstrated. At the highest dose (100 nM), E2 induced genes enriched not only for cell adhesion but also steroid hormone signaling and metabolism, cytokines and their receptors, cell-to-cell communication, Wnt signaling, and TGF- signaling. These results suggest that prostate mesenchymal cells may regulate epithelial cells through direct cell contacts when estrogen level is low whereas soluble growth factors might play significant roles when estrogen level is high.
Dose-related estrogen effects on gene expression in fetal mouse prostate mesenchymal cells.
Sex, Specimen part
View SamplesThe generation of induced pluripotent stem cells (iPSCs) often results in aberrant silencing of the imprinted Dlk1-Dio3 gene cluster, which compromises their ability to generate entirely iPSC-derived mice (all-iPSC mice). Here, we show that reprogramming in the presence of ascorbic acid attenuates hypermethylation of Dlk1-Dio3 by enabling a chromatin configuration at its imprint control region that interferes with abnormal binding of the DNA methyltransferase Dnmt3a. This approach allowed us to generate adult all-iPSC mice from mature B cells, which have thus far failed to support the development of exclusively iPSC-derived postnatal mice. Our data demonstrate that factor-mediated reprogramming can endow a defined, terminally differentiated cell type with a developmental potential equivalent to that of embryonic stem cells. More generally, these findings indicate that the choice of culture conditions used for transcription factor-mediated reprogramming can strongly influence the epigenetic and biological properties of resultant iPSCs.
Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells.
Specimen part, Treatment
View SamplesmiRNA abnormalities are increasingly relevent to cancer development, We used microarrays to detail the global programme of gene expression upon miR-483 overexpression in sarcoma cell line MHH-ES-1.
The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis.
Cell line, Treatment
View SamplesLymphoblastoid cell lines (LCLs), originally collected as renewable sources of DNA, are now being used as a model system to study genotype-phenotype relationships in human cells. These cell lines have been used to search for genetic variants that are associated with drug response as well as with more basic cellular traits such as RNA levels. In setting out to extend such studies by searching for genetic variants contributing to drug response, we observed that phenotypes in LCLs were, in our lab and others, significantly affected by experimental confounders (i.e. in vitro growth rate, metabolic state, and relative levels of the Epstein-Barr virus used to transform the cells). As we did not find any SNPs associated with genome-wide significance to drug response, we evaluated whether incorporating RNA expression levels (and eQTLs) in the analysis could increase power to detect such effects. As previously shown, cis-acting eQTLs were detectable for a sizeable fraction of RNAs and baseline levels of many RNAs predicted response to several drugs. However, we found only limited evidence that SNPs influenced drug response through their effect on expression of RNA. Efforts to use LCLs to map genes underlying cellular traits will require great care to control experimental confounders, unbiased methods for integrating and interpreting such multi-dimensional data, and much larger sample sizes than have been applied to date.
Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines.
No sample metadata fields
View Samples