Glucocorticoids delay RAF-induced senescence promoted by EGR1
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE134747 | GEO | 2019/08/27
REPOSITORIES: GEO
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Project description:Analysis of the differential binding of EGR1 to chromatin in human fibroblasts entering oncogene-induced senescence, with and without clobetasol.
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Project description:Glucocorticoids delay RAF-induced senescence promoted by EGR1
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Project description:Glucocorticoids delay RAF-induced senescence promoted by EGR1 [ChIP-seq]
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Project description:Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA-sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and Agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, Agrin-induced senescence and repair require Egr1, activated by the integrin/FAK-ERK/Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype (SASP) components that promote ECM degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.
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Project description:This experiment was designed to study oncogene-induced senescence (OIS). To this end we generated a series of cell lines derived from normal human diploid fibroblasts IMR90 forced to express the catalytic subunit of telomerase (hTERT). This cells were then subjected to further manipulation by orderly introducing defined genetic elements by retroviral transduction. The first cell line generated was ITV, which was obtained from the original cell line (IMR90 with hTERT) after introducing an empty vector. Subsequently, we introduced Mek:ER, which is a switchable version of the Mek kinase, a relevant downstream effector of Ras signaling during Ras-induced senescence, to generate ITM cells. We further modified this cell line by introducing SV40 small-t antigen (ST), papillomavirus oncoproteins E6 and E7 (E6/E7) or the combination of both (E6/E7 and ST). In this manner, we obtained ITMST, ITME6E7 and ITME6E7ST respectively. This cellular system allow us to have a representation of the different steps into neoplastic transformation. ITM and ITMST cells respond to Mek activation by inducing OIS. ITME6E7 and ITME6E7ST cells do not enter OIS after Mek activation. Mek activation is achieved by treating all cell cultures with 4-hydroxytamoxifen (4OHT) at 100 nM, in the absence of serum, and for 3 days. The gene expression profile of ITV cells served as a reference for all the expression values obtained with the rest of the cell lines. Thus, we ended up with the expression profiles of two cell lines representing oncogene-induced senescence (ITM and ITMST), and two cell lines representing bypass of oncogene-induced senescence, plus a reference profile provided by ITV, the cell line from which all the other cell lines were derived. Our final goal was to identify markers of the oncogene-induced senescence response by comparing the expression profiles of the cell lines entering OIS after Mek activation (that is, after 4OHT treatment) with the ones bypassing this response. Keywords: other
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Project description:The protein signatures in two mouse models of cardiac regeneration reveal enriched senescence gene sets, and Egr1 is the key regulator for regenerative senescence.Cathepsin S, a regenerative senescence-secreted component, promotes the degradation of the extracellular matrix, contributing to cardiac repair.
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Project description:Hypoxia increases histone methylation by inhibiting O2- and a-ketoglutarate-dependent histone lysine demethylases (KDMs). This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping, and heterochromatin redistribution (senescence-associated heterochromatin foci, SAHF) found during oncogene-induced senescence (OIS). Raf activation in primary human fibroblasts IMR90 increased cathepsin L (CTSL)-mediated clipping of histone 3 (H3), H2B and H4 at H3 A21/T22, H2B T19/K20, and H4 G11/K12, respectively. Hypoxia protected H3 from CTSL by increasing histone methylation, especially at H3K23me3 without reducing the activity of CTSL. The maintenance of methylated histones is sufficient for protecting histones from CTSL, not sufficient but necessary for inhibiting SAHFs. Expression of cleaved H3 induces senescence even under hypoxia, suggesting that hypoxia disrupts this positive feedback loop of OIS by increasing histone methylation. Thus, hypoxia protects histones and chromatin from dramatic epigenetic changes by increasing histone methylation. These observations suggest that the OIS process increases the accessibility of chromatin, which hypoxic conditions inhibited.
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Project description:Hypoxia in stem cell niches and inner core of solid tumors contributes to cellular senescence and differentiation inhibition. It directly increases histone methylationby inhibiting the activities of O2-and α-ketoglutarate (α-KG)-dependent histone lysine demethylases. This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). This study showed that Raf activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated cleavage of H3, H2B, and H4. Hypoxia prevented H3 cleavage not by inhibiting CTSL but by increasing H3K18me3 and H3K23me3 nearby cleaved site of H3. Forced expression of cleaved H3 in IMR90 cells induced senescence even under hypoxia, suggesting that hypoxia breaks this positive feedback senescence driving circle by increasing methylated histones. The decrease in methylated histones is necessary for OIS to trigger histone clipping and SAHFs, but hypoxia maintains methylated histones to prevent both. Forced reduction of methylated histones in hypoxic cells using inhibitors of methyl-transferases makes hypoxic conditions unable to prevent OIS from inducing both histone clipping and SAHFs. Reversely forced enhancement of methylated histones in normoxic cells using inhibitors of histone demethylases protected histones from clipping during OIS but failed to block SAHFs. Altogether, the maintenance of methylated histones, especially H3K23me3 and H3K18me3, is sufficient to protect histones from clipping during OIS, but not for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other methods to inhibit SAHFs. These findings provide a novel mechanism by which hypoxia affects cell fate by increasing methylated histones that protect histones and chromatin from dramatic epigenetic changes.
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Project description:Oncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought. Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary senescence compared to OIS point towards a functional diversification.
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