RNA profiling of p16ink4a-expressing pancreatic beta-cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76992 | GEO | 2016/01/20
SECONDARY ACCESSION(S): PRJNA309188
REPOSITORIES: GEO
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Project description:We collected freshly sorted mesenchyme (live CD45-Epcam-CD31-PDGFRa+GFP- or GFP+) from dissociated lung tissue of INKBRITE animals to characterize the transcriptome difference between p16INK4a+ vs p16INK4a- cells at homeostasis and during injury. We used fluorescence activated cell sorting (FACS) to exclude immune (CD45+), epithelial (Epcam+), and endothelial (CD31+) cells and positively select for PDGFRa+ mesenchyme. Cells were sequenced at a depth of average of 45 million reads/sample. The results revealed an increase of senescence associated secretory phenotype (SASP) signature in p16INK4+ cells that becomes refined after injury. We found the expression of an epithelial growth factor epiregulin (ereg) increased in p16INK4a+ cells after injury suggesting a possible role of p16INK4a+ senescence during regeneration of lung epithelium.
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Project description:In this study we examine the outcomes of p16INK4a activation in the adult epidermis. We found that prolonged expression of p16INK4a induces epidermal hyperplasia and dysplasia. We also found that continued p16INK4a expression increased the number of epidermal papillomas that developed after carcinogen treatment. Profling of p16INK4a- expressing cells showed elevated levels of Wnt-pathway ligands and targets, and pharmacologic or genetic Wnt inhibition suppressed p16-induced hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16-expressing cells are typically found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that in addition to its cell-autonomous role in blocking cell proliferation, p16 can induce hyperplasia through paracrine stimulation, suggesting that its activity contributes to the formation of early premalignant epidermal lesions.
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Project description:In this study we examine the outcomes of p16INK4a activation in the adult epidermis. We found that prolonged expression of p16INK4a induces epidermal hyperplasia and dysplasia. We also found that continued p16INK4a expression increased the number of epidermal papillomas that developed after carcinogen treatment. Profling of p16INK4a- expressing cells showed elevated levels of Wnt-pathway ligands and targets, and pharmacologic or genetic Wnt inhibition suppressed p16-induced hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16-expressing cells are typically found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that in addition to its cell-autonomous role in blocking cell proliferation, p16 can induce hyperplasia through paracrine stimulation, suggesting that its activity contributes to the formation of early premalignant epidermal lesions.
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Project description:Cellular senescence plays a causal role in ageing and, in mouse, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders. Adenosine deaminases acting on RNA (ADARs) RNA editing enzymes are also implicated as important regulators of human ageing and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through upregulating p16INK4a. ADAR1 is downregulated during senescence post-transcriptionally by autophagy-lysosomal pathway and the downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a dependent and independent of its RNA editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA binding protein that increases the half-life and steady state levels of its target mRNAs. And SIRT1, in turn, antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4aupregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary, and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing independent role of ADAR1 in regulating senescence by post-transcriptionally controlling p16INK4a expression.
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Project description:In this study, we generated a novel nuclear-localized red fluorescence knock-in reporter allele (Ins2.Apple) for mouse pancreatic beta-cells. Beta-cells were isolated by FACS from 60-day-old mice, segregated by sex, and RNA-sequencing was performed to assess sex-specific differences in beta-cell gene expression profiles. We also isolated beta-cells (by FACS) from MIP-GFP mice at 60 days of age. RNA-sequencing was performed, and was compared to that of Ins2.Apple beta cells, to assess gene expression changes brought on by the presence of the MIP-GFP transgene.
2018-12-15 | E-MTAB-6329 | biostudies-arrayexpress
Project description:RNA profiling of p16ink4a-expressing pancreatic beta-cells
| PRJNA309188 | ENA