Cellular senescence is an irreversible proliferative arrest and can be triggered in many cell types in response to diverse forms of cellular damage or stress.
Senescence of activated stellate cells limits liver fibrosis.
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View SamplesThe p53 protein is a cell-autonomous tumor suppressor that restricts malignant transformation by triggering cell cycle exit or apoptosis. p53 also promotes cellular senescence, a program that triggers a stable cell cycle arrest and can modify the tissue microenvironment through its effect on cell membrane and secretory proteins. Here we show that specific ablation of p53 in hepatic stellate cells, which undergo a process of proliferation and senescence in the fibrogenic response to liver damage, enhances liver cirrhosis, reduces survival and increases the malignant transformation of adjacent epithelial cells into hepatocellular carcinoma. This p53-dependent senescence program involves the release of secreted proteins which skew macrophages into a tumor-inhibiting M1-state that can eliminate senescent stellate cells. In contrast, p53-deficient stellate cells secrete factors that promote M2 polarization, which is pro-tumorigenic. Our study reveals that p53 can exert a non-cell-autonomous tumor suppressor response and suggests that this occurs, in part, by its ability to influence macrophage polarization.
Non-cell-autonomous tumor suppression by p53.
Specimen part, Treatment
View SamplesUterine tissue is highly responsive to estrogen, which plays a mayor role in sympathetic innervation remodeling in myometrium
Neurotrimin is an estrogen-regulated determinant of peripheral sympathetic innervation.
No sample metadata fields
View SamplesTranscription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition sites to be the most depleted and enriched sequences, respectively, in the sense direction relative to the upstream antisense direction. These U1 snRNP sites and PAS sites are progressively gained and lost, respectively, at the 5'' end of coding genes during vertebrate evolution. Functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction. These data suggest that a U1-PAS axis characterized by low U1 snRNP recognition and a high density of PASs in the upstream antisense region reinforces promoter directionality by promoting early termination in upstream antisense regions, whereas proximal sense PAS signals are suppressed by U1 snRNP. We propose that the U1-PAS axis limits pervasive transcription throughout the genome. Overall design: 3'' end sequencing of poly (A) + RNAs in mouse ES cells with and without U1 snRNP inhibition using antisense morpholino oligonucleotides (AMO). Each with two biological replicates.
Promoter directionality is controlled by U1 snRNP and polyadenylation signals.
Cell line, Treatment, Subject
View SamplesUncontrolled microglial activation may lead to development of inflammation-induced brain damage. Here we uncover a ribosome-based mechanism/check point involved in control of the innate immune response and microglial activation. Using an in vivo model-system for analysis of the dynamic translational state of microglial ribosomes with mRNAs as input and newly synthesized peptides as an output, we find a marked dissociation of microglia mRNA and protein networks following innate immune challenge. Highly up-regulated and ribosome-associated mRNAs were not translated resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA and immunomodulatory/homeostatic protein signature. We find that this is due to specific translational suppression of highly expressed mRNAs through a 3UTR-mediated mechanism involving the RNA binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia.
Diverging mRNA and Protein Networks in Activated Microglia Reveal SRSF3 Suppresses Translation of Highly Upregulated Innate Immune Transcripts.
Treatment
View SamplesThere is an association between transcriptome and the exercise-related phenotype. Peripheral blood cells suffer alterations in the gene expression pattern in response to perturbations caused by exercise. The acute response to endurance activates stress and inflammation, as well as growth and tissue repair responses.
PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men.
Sex, Specimen part, Disease, Disease stage, Treatment, Subject, Time
View SamplesMammalian nephrons are the physiological subunits of mammalian kidneys which consist of different highly apicobasally polarized epithelial cell types. In epithelial cells polarization is controlled by evolutionary conserved CRB, PAR, or SRIB complexes. Here, we focused on the role of Pals1/Mpp5 in the nephron. Pals1, a core component of the apical membrane determining CRB complex, is highly expressed in renal tubular epithelial and glomerular epithelial cells (podocytes). Surprisingly, haplo-deficient mice, lacking one Pals1/Mpp5 allele in the nephron developed a strong phenotype, accompanied by cyst formation and severe renal filtration barrier defects, which subsequently lead to death after 6-8 weeks. Supporting studies in Drosophila nephrocytes, and epithelial cell culture models elucidated the role of Pals1 as a dose dependent upstream regulator of the crosstalk between Hippo- and TGF-signaling during nephrogenesis.
Pals1 Haploinsufficiency Results in Proteinuria and Cyst Formation.
Specimen part
View SamplesA limited number of growth factors are capable of regulating numerous developmental processes, but how they accomplish this is unclear. In the gustatory system, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) have different developmental roles but exert their effects through the same receptors (TrkB and p75).
BDNF and NT4 play interchangeable roles in gustatory development.
Specimen part
View SamplesThe root apex is an important section of the plant root, involved in environmental sensing and cellular development. Analyzing the gene profile of root apex in diverse environments is important and challenging, especially when the samples are limiting and precious, such as in spaceflight. The feasibility of using tiny root sections for transcriptome analysis was examined in this study.To understand the gene expression profiles of the root apex, Arabidopsis thaliana Col-0 roots were sectioned into Zone-I (0.5 mm, root cap and meristematic zone) and Zone-II (1.5 mm, transition, elongation and growth terminating zone). Gene expression was analyzed using microarray and RNA seq.Both the techniques, arrays and RNA-Seq identified 4180 common genes as differentially expressed (with > two-fold changes) between the zones. In addition, 771 unique genes and 19 novel TARs were identified by RNA-Seq as differentially expressed which were not detected in the arrays. Single root tip zones can be used for full transcriptome analysis; further, the root apex zones are functionally very distinct from each other. RNA-Seq provided novel information about the transcripts compared to the arrays. These data will help optimize transcriptome techniques for dealing with small, rare samples. Overall design: Arabidopsis thaliana var. Columbia (COL-0) seedlings were grown on sterile solid media plates containing 0.5 % phytagel. The plates were vertically placed in growth chambers with continuous light (80-100 µmol m -2) at a constant temperature of 19° C. Eight day old seedlings were harvested into RNA-later solution in a 50 mL centrifuge tubes and stored at -20 °C freezer. The root tips were dissected into zone-I: 0.5mm from the tip including the root cap and root division zones, and zone-II: 1.5mm sections including root elongation and root hair zone. Microarray and sequencing experiments were performed.
Comparing RNA-Seq and microarray gene expression data in two zones of the <i>Arabidopsis</i> root apex relevant to spaceflight.
Age, Specimen part, Subject
View SamplesA growing body of evidence suggests that the vasoactive peptides endothelins (ETs) and their receptors (primarily the ETB receptor) are contributors to neurodegeneration in glaucoma. However, ETs actions in retinal ganglion cells (RGCs) are not fully understood. The purpose of this study was to determine ETs effects on gene expression in primary RGCs.
Endothelin-Mediated Changes in Gene Expression in Isolated Purified Rat Retinal Ganglion Cells.
Specimen part
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