Similar Datasets
Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces âÂÂSASP-likeâ inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study consists of a single replicate of RNA-seq from oncogene-induced senescent (or control) IMR90 cells in a MLL1 knockdown (or WT) background, for a total of four samples
2016-02-23 | E-GEOD-78138 | biostudies-arrayexpress
Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces �SASP-like� inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).
2016-02-23 | E-GEOD-78141 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces âSASP-likeâ inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. Previously published samples GSM1135046, GSM1135044, GSM1135047, and GSM1135045 were also studied in this investigation and appear in GSE36641. This did not involve re-sequencing or re-alignment, nor any other deviation from the data protocols in that series. Refer to individual Series
2016-02-22 | E-GEOD-78142 | biostudies-arrayexpress
Project description:This study investigates the effects of hyperbaric oxygen (HBO) on cellular senescence and aging-related phenotypes. In naturally aged mice, HBO treatment reduced systemic senescence burden and reversed aging-related transcriptomic signatures in skin, liver, and kidney tissues. Additionally, single-session HBO exposure was shown to preferentially suppress SASP propagation in human stromal cells. This dataset includes transcriptomic profiles of skin, liver, and kidney tissues from young, aged, and HBO-treated aged mice, as well as human primary prostate stromal cells (PSC27).
2025-05-09 | GSE296209 | GEO
Project description:Here we report that TET1 has a critical role in B-ALL development. TET1-depleted cells delayed the onset of B-ALL. To investigate the mechanisms, we first generate the patient-derived xenograft cells (PDX2) and transduce with inducible-Cas9 and sgRNA targeting TET1. After treatment with doxycycline, we observe the expression of Cas9 and a depletion of TET1 protein. By using the high throughput sequencing RNA-seq, we check the potential targets of TET1 in B-ALL cells. Finally, we validate that CD72 and JCHAIN are two essential targets of TET1 signaling in B-ALL cells.
2023-02-13 | GSE190851 | GEO
Project description:We performed calibrated ChIP-seq, PRO-seq, TT-seq, or RNA-seq to investigate the role of protein phosphotase PNUTS-PP1 in regulating transcription. ChIP-seq, PRO-seq, TT-seq, or RNA-seq were normalizated by MEF as spike-in. The reads passed the quality check aligned to the human hg19 and mouse mm10 genome. In this study, samples for each condition were collected in biological duplicates. Cells were treated with dTAG13 for 3,12h, the corresponding control cells were treated with vehicle only (DMSO) at the same vol/vol dilution.
2024-12-02 | GSE280548 | GEO
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined gentotype (NI, Nf1-/-;Ink4a/Arf-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, or trametinib and SHP099 in combination for 5, 15, or 28 days to evaluate the effects on the functional kinome.
2024-11-20 | PXD035998 | Pride
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined genotype (NP, Nf1-/-;Trp53-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, trametinib, or trametinib and SHP099 in combination for 5 or 21 days to evaluate the effects on the functional kinome.
2024-11-20 | PXD035999 | Pride
Project description:Cellular senescence is a stable cell growth arrest that is characterized by silencing of proliferation-promoting genes through compaction of individual chromosomes into senescence-associated heterochromatin foci (SAHF). Paradoxically, senescence is also accompanied by increased expression of certain secreted factors such as cytokines and chemokines, known as senescence-associated secretory phenotype (SASP). How SASP genes are excluded from SAHF-mediated global gene silencing remains unclear. Here we report that HMGB2 orchestrates the chromatin landscape of SASP gene loci. HMGB2 preferentially localizes to SASP gene loci during senescence. Loss of HMGB2 during senescence blunts SASP gene expression by allowing for spreading of repressive heterochromatin into SASP gene loci. This correlated with incorporation of SASP gene loci into SAHF. Our results establish HMGB2 as a novel master regulator that orchestrates SASP through preventing heterochromatin spreading to allow for exclusion of SASP gene loci from a global heterochromatin environment during senescence.
2016-10-11 | GSE85057 | GEO
Project description:The RNA-binding protein AU-rich-element factor-1 (AUF-1) regulates mRNA decay and translation of genes during inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine-challenged airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function. RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human BEAS-2B cell line, 494 AUF-1-bound mRNAs enriched in their 3’-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif, selectively confirmed by biotin pulldown. AUF-1-targets’ steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNF/IL1/IFN/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-decreased AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) associated with cell-cycle arrest, increased lysosomal damage and senescence-associated secretory phenotype (SASP) factors and with increased AUF-1 in extracellular vesicles. In-silico analysis found enriched AUF-1-targets in COPD-related pathways, SASP proteome atlas, transcriptomic COPD databases of HSAEC, lung tissue and single-cell RNA-sequencing. Intracellular and exosomal-associated AUF-1 may mediate airway epithelial inflammatory responses.
2023-04-14 | E-MTAB-12583 | biostudies-arrayexpress