The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (Treg cells). To gain insights into the molecular mechanisms of Foxp3 mediated gene expression we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multi-protein complexes of 400-800 kDa or larger and identified 361 associated proteins ~30% of which are transcription-related. Foxp3 directly regulates expression of a large proportion of the genes encoding its co-factors. Reciprocally, some transcription factor partners of Foxp3 facilitate its expression. Functional analysis of Foxp3 cooperation with one such partner, Gata3, provided further evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of Treg cell biology.
Transcription factor Foxp3 and its protein partners form a complex regulatory network.
Specimen part
View SamplesdMyc is a conserved transcription factor that controls growth and proliferation by regulating its target genes.
MicroRNA miR-308 regulates dMyc through a negative feedback loop in Drosophila.
Specimen part
View SamplesA major role of NINJA is to repress root jasmonate signalling and allow normal cell elongation.
Multilayered Organization of Jasmonate Signalling in the Regulation of Root Growth.
Specimen part
View SamplesThe traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers.
Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1.
Sex, Specimen part
View SamplesTrisomy 21 (Ts21) or Down syndrome (DS) is the most common genetic cause of intellectual disability. To investigate the consequences of Ts21 on human brain development, we have systematically analyzed the transcriptome of dorsolateral prefrontal cortex (DFC) and cerebellar cortex (CBC) using exon array mapping in DS and matched euploid control brains spanning from prenatal development to adulthood. We identify hundreds of differentially expressed (DEX) genes in the DS brains, many of which exhibit temporal changes in expression over the lifespan. To gain insight into how these DEX genes may cause specific DS phenotypes, we identified functional modules of co-expressed genes using several different bioinformatics approaches, including WGCNA and gene ontology analysis. A module comprised of genes associated with myelination, including those dynamically expressed over the course of oligodendrocyte development, was amongst those with the great levels of differential gene expression. Using Ts65Dn mouse line, the most common rodent model of DS, w e observed significant and novel defects in oligodendrocyte maturation and myelin ultrastructure; establishing a correlative proof-of-principle implicating myelin dysgenesis in DS. Thus, examination of the spatio-temporal transcriptome predicts specific cellular and functional events in the DS brain and is an outstanding resource for determining putative mechanisms involved in the neuropathology of DS.
Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.
Sex, Disease, Race
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Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver.
Sex, Treatment
View SamplesThe process of liver regeneration can be divided into a series of stages that include initial inductive or priming events through cellular mitosis. Following two-thirds liver resection, the liver undergoes the priming phase, in which cytokines TNF-a and IL-6 activate their respective receptors in hepatocytes. This leads to the activation of several key transcription factors: NF-kB, AP-1, Stat 3, Stat 1, and C/EBP-b and -d . These transcription factors induce the expression of immediate early genes. HGF is also expressed at this time and involved in the transition of quiescent hepatocytes into the G1 phase of the cell cycle. During the G1 phase, delayed early genes are expressed followed by induction of cell cyclerelated genes, both of which require new protein synthesis for their production. Increased expression of FoxM1B and TGF-a occurs at the G1/S transition and is correlated with increased expression of cyclinD1 and decreased expression of cdk inhibitors. During the G2/M phase of the cell cycle, FoxM1B directly elevates cyclinB1, cyclinB2, and cdc25B expression. Additionally, FoxM1B is associated with increased cyclinF and p55cdc, which are involved in completion of the cell cycle following partial hepatectomy. In mice, two-thirds partial hepatectomy promotes proliferation of liver cells and rapid growth of the remaining liver tissue, resulting in complete restoration of organ mass in approximately 7 days (Mackey S. et al. Hepatology 2003 Dec;38(6):1349-52).
Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver.
Sex, Treatment
View SamplesThe process of liver regeneration can be divided into a series of stages that include initial inductive or priming events through cellular mitosis. Following two-thirds liver resection, the liver undergoes the priming phase, in which cytokines TNF-a and IL-6 activate their respective receptors in hepatocytes. This leads to the activation of several key transcription factors: NF-kB, AP-1, Stat 3, Stat 1, and C/EBP-b and -d . These transcription factors induce the expression of immediate early genes. HGF is also expressed at this time and involved in the transition of quiescent hepatocytes into the G1 phase of the cell cycle. During the G1 phase, delayed early genes are expressed followed by induction of cell cyclerelated genes, both of which require new protein synthesis for their production. Increased expression of FoxM1B and TGF-a occurs at the G1/S transition and is correlated with increased expression of cyclinD1 and decreased expression of cdk inhibitors. During the G2/M phase of the cell cycle, FoxM1B directly elevates cyclinB1, cyclinB2, and cdc25B expression. Additionally, FoxM1B is associated with increased cyclinF and p55cdc, which are involved in completion of the cell cycle following partial hepatectomy. In mice, two-thirds partial hepatectomy promotes proliferation of liver cells and rapid growth of the remaining liver tissue, resulting in complete restoration of organ mass in approximately 7 days (Mackey S. et al. Hepatology 2003 Dec;38(6):1349-52).
Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver.
Sex, Treatment
View SamplesAge-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened life-span. Using highly purified hematopoietic stem cells from mice aged 2 to 21 months, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1500 that were age-induced and 1600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the upregulated expression profile, while the downregulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation, and an overall increase in transcriptional activity with aged, and inappropriate expression genes normally regulated by epigenetic mechanisms was observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that HSC are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.
Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation.
No sample metadata fields
View SamplesMyelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the contribution of these autoreactive T cells to disease pathology remains unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6+ myelin-reactive T cells from patients with MS exhibited significantly enhanced production of IFN-?, IL-17, and GM-CSF compared to healthy controls. Single-cell clones isolated by MHC/peptide tetramers from CCR6+ T cell libraries also secreted more pro-inflammatory cytokines while clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6+ T cells from patients with MS were distinct from those derived from healthy controls, and of note, were enriched in Th17-induced experimental autoimmune encephalitis (EAE) gene signatures and gene signatures derived from Th17 cells isolated other human autoimmune diseases. These data, although not casual, imply that functional differences between antigen specific T cells from MS and healthy controls is fundamental to disease development and support the notion that IL-10 production from myelin-reactive T cells may act to limit disease progression, or even pathogenesis. Overall design: Four conditions of purified T cells with between 3 and 5 replicates per condition
Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis.
No sample metadata fields
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