Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between these two pathways by identifying their common target genes and exploring potential underlying molecular mechanisms in human MCF7 breast cancer cells. Principal Findings: Gene expression profiling revealed that the expression of approximately 150 genes was influenced by both 17-estradiol (E2) and a hypomethylating agent 5-aza-2-deoxycytidine (DAC). Based on gene ontology (GO), CpG island prediction analysis and previously reported estrogen receptor (ER) binding regions, we selected six genes for further analysis (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2). GO analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis, while CpG island prediction of promoter regions reveals that the promoters of these genes contain at least one CpG island. Using chromatin immunoprecipitation, we show that ER is recruited to CpG islands in promoters, but neither in an E2- nor in a DAC-dependent fashion. DAC treatment reactivates the expression of all selected genes although only the promoters of BTG3 and FHL2 genes are methylated, with E2 treatment showing no effect on the methylation status of these promoters. Conclusions: We identified a set of genes regulated by both estrogen signaling and DNA methylation. However, our data does not support a direct molecular interplay of mediators of estrogen and epigenetic signaling at promoters of regulated genes.
Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells.
Cell line
View Samples10 male subjects performed ~45 min one-legged cycling and 4 x 7 maximal concentric-eccentric knee extensions for each leg 15 min later. Thus, one limb performed aerobic and resistance exercise (AE+RE), while the opposing leg did resistance exercise only (RE). Biopsies were obtained from m. vastus lateralis of each leg 3 h after the resistance exercise bout.
Aerobic exercise augments muscle transcriptome profile of resistance exercise.
Sex, Specimen part, Treatment, Subject
View SamplesMitotic entry is accompanyed by the expression of a cluster of so called mitotic genes, whose activation is critical for mitosis in human and yeast cells. We found a link between the transcription machinery and cell cycle control network at mitosis in fission yeast, involving the Cdk8 kinase dependent phosphorylation of the fork head transcription factor Fkh2. We have generated a non-phosphorylatable fkh2 mutant (fkh2-S2A) also.
Cyclin-dependent kinase 8 regulates mitotic commitment in fission yeast.
No sample metadata fields
View SamplesExpression profiling of proliferating primary myoblasts obtained from vastus lateralis muscle biopsises from healthy individuals and stimulated with Vitamin D (100 nM 1,25(OH)2D3) or vehicle for 24h.
Evidence for Vitamin D Receptor Expression and Direct Effects of 1α,25(OH)2D3 in Human Skeletal Muscle Precursor Cells.
Specimen part, Treatment, Subject
View SamplesWe have used microarrays to study the gene expression changes in Overexpression of GST,GST-Med3 of yeast cells to detect how the overexpressioin may affect global gene expression.
Mediator tail subunits can form amyloid-like aggregates in vivo and affect stress response in yeast.
No sample metadata fields
View SamplesChemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer's stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor ß variants, ß2 and ß5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1a and HIF-2a is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor ß variants, estrogen receptor ß2 and ß5, bind to and stabilize both HIF-1a and HIF-2a proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor ß variants, ß2 and ß5, could be involved in development of a cancer's stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion. Overall design: Examination of the transcriptome changed by two estrogen reseptor beta variants (ERbeta2 and ERbeta5). Control (lacking expression) and variant expressing cells in two repeats
The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling.
Specimen part, Subject
View SamplesAffymetrix human whole transcriptome array (HTA 2.0) completed on patients with Crohn's disease undergoing their first ileocolic resection
Predicting Risk of Postoperative Disease Recurrence in Crohn's Disease: Patients With Indolent Crohn's Disease Have Distinct Whole Transcriptome Profiles at the Time of First Surgery.
Specimen part
View SamplesThe multiprotein Mediator complex is an important regulator of RNA polymerase II-dependent genes in eukaryotic cell. In contrast to the situation in many other eukaryotes, the conserved Med15 protein is not a stable component of Mediator isolated from fission yeast. We now demonstrate that Med15 exists in a protein complex together with Hrp1, an ATP-dependent chromatin remodeling protein. The Med15/Hrp1 subcomplex is not a component of the core Mediator complex, but can interact with the repressive L-Mediator conformation. Deletion of MED15 and HRP1 cause similar effects on global steady-state levels of mRNA, but only MED15 is required for galactose-dependent activation of the inv1 gene. Hrp1 has been found in complex with other proteins and genome-wide analysis demonstrates that Med15 only associates with a distinct subset of Hrp1-bound gene promoters. Global analysis reveals that Hrp1-binding normally is associated with increased histone H3 density, but at promoters also bound by Med15, histone H3 density is instead increased. Our findings reveal that Med15 functions as a separate entity in fission yeast and indicate that the function and organization of the Mediator complex may differ significantly between eukaryotes.
A chromatin-remodeling protein is a component of fission yeast mediator.
No sample metadata fields
View SamplesThe aim of this work was to produce a reproducible molecular signature of human muscle responses to resistance training and examine how such a profile relates to new and established exercise adaptation gene networks.
Molecular networks of human muscle adaptation to exercise and age.
Age, Specimen part, Subject, Time
View SamplesThe overall objective of the heritage project is to study the role of the genotype in cardiovascular,metabolic and hormonal responses to aerobic exercise training and the contribution of regular exercise to changes in several cardiovascular disease and diabetes risk factors.
Molecular networks of human muscle adaptation to exercise and age.
Age, Specimen part, Subject, Time
View Samples