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Gene expression changes in fibroblasts with constitutively active Nrf2 reflect a senescence-associated secretory phenotype (SASP)

ABSTRACT: Gene expression changes in fibroblasts with constitutively active Nrf2 reflect a senescence-associated secretory phenotype (SASP)

PROVIDER: PRJNA415598 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6207350.fastq.gz	Fastqsanger.gz
	SRR6207351.fastq.gz	Fastqsanger.gz
	SRR6207352.fastq.gz	Fastqsanger.gz
	SRR6207347.fastq.gz	Fastqsanger.gz
	SRR6207348.fastq.gz	Fastqsanger.gz

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Gene expression changes in fibroblasts with constitutively active Nrf2 reflect a senescence-associated secretory phenotype (SASP)

Project description:Nrf2 is a key regulator of the cellular antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention. Here we discovered a novel role of Nrf2 as a regulator of the matrisome. Activation of Nrf2 in fibroblasts induced early onset of cellular senescence. Mechanistically, this resulted from Nrf2-mediated transcription of matrix and matrix-remodeling genes. Fibroblasts with activated Nrf2 deposited a senescence-promoting matrix, with plasminogen-activator inhibitor being the key inducer of the senescence program. In vivo, this promoted keratinocyte proliferation and re-epithelialization during wound healing, but also skin tumorigenesis. Analysis of the gene expression profile of fibroblasts with activated Nrf2 and published data sets revealed that Nrf2 activates genes characteristic for cancer-associated fibroblasts. These data identify Nrf2 as a key player in the control of the cancer-associated fibroblast phenotype and highlight the need for careful use of Nrf2-activating pharmaceuticals.

2018-08-30 | GSE106097 | GEO

Mettl14-driven senescence-associated secretory phenotype (SASP) facilitates somatic reprogramming

Project description:The METTL3-METTL14 complex, as the "writer" of N6-methyladenosine (m6A), plays an important role in many biological processes. Previous studies have shown that overexpression of Mettl3 can increase the level of m6A and promotes somatic cell reprogramming. Here, we demonstrate that Mettl14, another component of the methyltransferase (MTase) complex, can significantly enhance the generation of induced pluripotent stem cells (iPSCs) in m6A independent manner. Cooperating with Oct4, Sox2, Klf4 and c-Myc (OSKM), Mettl14 transiently increased the senescence-associated secretory phenotype (SASP) gene expression in the non-reprogramming cells at the late reprogramming stage. The conditional medium in reprogramming intermediates overexpressing Mettl4 or its mutant could enhanced the reprogramming, so do IL-6, a component of SASP. Corespondingly, blocking of SASP using senolytic agent or NF-κB inhibitor impairs the effect of Mettl14 on reprogramming. . Our work highlights the m6A independent function of Mettl14 and provides new insight into the interplay between senescence and reprogramming in vitro.

2022-08-24 | GSE196475 | GEO

Mettl14-driven senescence-associated secretory phenotype (SASP) facilitates somatic reprogramming

Project description:Mettl14-driven senescence-associated secretory phenotype (SASP) facilitates somatic reprogramming

| PRJNA805125 | ENA

Unique human beta-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors

Project description:The aging of pancreatic beta-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging beta-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to beta-cell failure. Herein, we defined the beta-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from human senescent beta-cells. These experiments revealed that the beta-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species.

2021-03-18 | GSE162521 | GEO

Differentially regulated miRNAs in skin fibroblasts with constitutively active Nrf2

Project description:Differentially regulated miRNAs in skin fibroblasts with constitutively active Nrf2

| PRJNA748397 | ENA

Functional analysis of the cytoprotective transcription factor Nrf2 in keratinocytes: Identification of Nrf2-regulated miRNAs

Project description:Nrf2-regulated mRNAs are known; however, no Nrf2-regulated miRs have been identified miR microarray analysis from total RNA samples was performed to test which miRs are regulated by Nrf2 Total RNA from skin of mice with constitutively active Nrf2 (CMV-caNrf2), dominant-negative Nrf2 (dnNrf2), and correcponding control littermates (K5Cre(wt) for CMV-caNrf2 and wt for dnNrf2)

2015-01-01 | E-GEOD-52454 | biostudies-arrayexpress

MLL1 is essential for the senescence-associated secretory phenotype

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

Efficacy of small molecule inhibitors and genetic interference of cGAS-STING axis on development of the senescence-associated secretory phenotype (SASP) in human stromal cells

Project description:Rapid advancements in next generation sequencing (NGS) have revolutionized system-based analysis of genome-wide expression, cellular pathways and stress responses. We performed this cGAS-STING-associated study to streamline the transcriptomic profiling (RNA-seq) of human stromal cells manifesting a typical senescence-associated secretory phenotype (SASP) in a DNA damage setting.

2022-12-31 | GSE128420 | GEO

MLL1 is essential for the senescence-associated secretory phenotype [RNA-Seq]

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 Ã¢ÂÂSASP-likeÃ¢ÂÂ 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

Genome-wide transcript profiling of human prostate stromal cells in response to genotoxic treatment and SASP inhibitors

Project description:Cancer develops in a complex environment that encompasses a wide spectrum of benign cell types, while the local microenvironment reduces the efficacy of multiple forms of cancer therapies. The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in cellular senescence and the senescence-associated secretory phenotype (SASP), the side effects of the latter frequently fueling advanced pathologies particularly therapeutic resistance. However, candidate approaches to prevent or circumvent the SASP development remains limited. We treated PSC27, a primary normal human prostate stromal cell line, with the genoxotic agents hereby represented by bleomycin, to investigate the relevant mechanisms. In order to control the SASP development, a group of potential SASP inhibitors were applied including p38MAPK, mTOR and TAK1 suppressors. The purpose was to compare the efficacy and effectiveness of these chemicals in combinatin with typical anticancer drugs in minimizing the secretory phenotype upon DNA damage that functionally remodels human stromal cells.

2018-12-27 | GSE90866 | GEO

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