genes regualted by LPS or LPS+cAMP stimulation in BMDCs
Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the phosphorylated c-Fos protein.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
The transcriptional programme controlled by Runx1 during early embryonic blood development.
Specimen part, Cell line
View SamplesTranscription factors have long been recognised as powerful regulators of mammalian development, yet it is largely unknown how individual key regulators operate within wider regulatory networks. Here we have used a combination of global gene expression and chromatin-immunoprecipitation approaches across four ES-cell-derived populations of increasing haematopoietic potential to define the transcriptional programme controlled by Runx1, an essential regulator of blood cell specification. Integrated analysis of these complementary genome-wide datasets allowed us to construct a global regulatory network model, which suggested that core regulatory circuits are activated sequentially during blood specification, but will ultimately collaborate to control many haematopoietically expressed genes. Using the CD41/integrin alpha 2b gene as a model, cellular and in vivo studies showed that CD41 is controlled by both early and late circuits in fully specified blood cells, but initiation of CD41 expression critically depends on a later subcircuit driven by Runx1. Taken together, this study represents the first global analysis of the transcriptional programme controlled by any key haematopoietic regulator during the process of early blood cell specification. Moreover, the concept of interplay between sequentially deployed core regulatory circuits is likely to represent a design principle widely applicable to the transcriptional control of mammalian development.
The transcriptional programme controlled by Runx1 during early embryonic blood development.
Specimen part, Cell line
View SamplesThe adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist.
Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection.
Specimen part
View SamplesThe loss of REST in uterine fibroids promotes aberrant gene expression and enables mTOR pathway activation
Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.
Specimen part, Treatment
View SamplesUnderstanding the molecular underpinnings of cancer is of critical importance to developing targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features and induce complex changes in gene expression patterns. Genes critical to this multi-faceted cellular phenotype thus only have been identified following signaling pathway analysis or on an ad hoc basis. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signaling circuitry suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state. Remarkably, 14 among 24 such 'cooperation response genes' (CRGs) were found to contribute to tumor formation in gene perturbation experiments. In contrast, only one in 14 perturbations of genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain and loss-of-function mutations.
Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype.
No sample metadata fields
View SamplesThe mammalian circadian clock system is made up of individual cell and tissue clocks that function as a coherent network, however it remains unclear which rhythmic functions of the liver clock are autonomous or rely on clocks in other tissues. Here, using mice which only have a functioning liver clock, we investigate the autonomous vs non-autonomous reatures of the liver clock and diurnal rhythmicity in the liver Overall design: 8-12 week-old, female WT, KO and Liver-RE BMAL1-stop-FL mice (see referenced paper for details) were fed ad libitum normal chow under 12hr light/ 12hr dark schedule. Livers were harvested every 4 hours over the circadian cycle at ZT0, 4, 8, 12, 16, 20 (n=3 per time point per group). Total RNA was extracted and used for RNA-seq.
Defining the Independence of the Liver Circadian Clock.
Specimen part, Subject
View SamplesThe Ets transcription factor, ERG, plays a central role in definitive hematopoiesis and its overexpression in acute myeloid leukemia is associated with a stem cell signature and bad prognosis. However, little is known about the underlying mechanism by which ERG causes leukemia. Therefore we sought to identify ERG targets that participate in development of leukemia by integration of expression arrays and Chromatin immunoprecipitation.
Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia.
No sample metadata fields
View SamplesBy 2 weeks after stem cell transplantation, there was differentiated changes in T cell phenotype between autograft and allograft. RNA-seq was used to reveal the different transcription profiles of these T cells at week 2 after SCT. Overall design: Compare the transcription profile of the T cells in allograft and autograft transplantation patients.
Unique features and clinical importance of acute alloreactive immune responses.
Specimen part, Disease, Subject, Time
View SamplesPioneer transcription factors are able to recognise and bind their motif sequences in inaccessible or closed chromatin, and their ability to achieve this is required to establish new regulatory elements and transcriptional networks during development and cellular reprogramming. An essential feature of this pioneering activity is the transition from inaccessible chromatin to a nucleosome-depleted and accessible chromatin state typical of normal regulatory elements, and this is believed to facilitate further transcription factor binding events. However, the mechanisms by which many pioneer transcription factors achieve this remarkable feat remain elusive. Here we reveal that the pluripotency-associated pioneer factor OCT4 binds inaccessible chromatin to shape the chromatin accessibility, transcription factor co-binding and regulatory potential of thousands of distal regulatory elements in mouse embryonic stem cells, demonstrating that its pioneering activity is a feature of normal pluripotency, and not just reprogramming. The accessible chromatin formed at OCT4 binding sites relies on the chromatin remodelling factor BRG1, which is recruited to these sites by OCT4. The occupancy of BRG1 is then required to support OCT4/SOX2 co-binding and normal expression of the pluripotency-associated transcriptome, and this reliance on BRG1 reflects OCT4 binding dynamics during cellular reprograming and early mouse development. Together these observations reveal a distinct requirement for the chromatin remodelling factor BRG1 in shaping the pioneering activity of OCT4 and regulating the pluripotency network in embryonic stem cells. Overall design: ZHBTC4 and Brg1fl/fl mouse embryonic stem cells were used to ablate OCT4 and BRG1 expression respectively, followed by ATAC-seq, ChIP-seq or RNA-seq to examine their contribution towards chromatin accessibility, transcription factor occupancy, and gene expression.
The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells.
Cell line, Treatment, Subject
View Samples